BBT-877, a Novel Autotaxin Inhibitor, Abrogates Drug Resistance in Epithelial Ovarian Cancer Stem Cells.

BACKGROUND/AIM: Cancer stem cells (CSCs) contribute significantly to the poor prognosis of patients with epithelial ovarian cancer (EOC) due to their roles in drug resistance and tumor metastasis. Autotaxin (ATX) plays a pivotal role in the maintenance of the CSC-like properties of EOC tumors. BBT-877 is a novel ATX inhibitor used in clinical treatment of idiopathic pulmonary fibrosis. However, the effects of BBT-877 on drug resistance and metastasis in ovarian CSCs remain unknown. In this study, we aimed to investigate the effects of BBT-877 on drug resistance and intraperitoneal metastasis of EOC. MATERIALS AND METHODS: Spheroid-forming CSCs, which were isolated from two EOC cell lines, A2780 and SKOV3, were investigated by cell viability, western blot, PCR, Spheroid-forming assay, and in vivo experiments. RESULTS: Spheroid-forming CSCs exhibited increased CSC-like properties and paclitaxel (PTX) resistance. BBT-877 treatment inhibited the viability of spheroid-forming CSCs more potently than that of adherent ovarian cancer cell lines. Combinatorial treatment with BBT-877 and PTX significantly attenuated the viability of spheroid-forming CSCs. In a SKOV3 cells-derived intraperitoneal metastasis model, BBT-877 treatment reduced the number of metastatic tumor nodes, while combinatorial treatment with BBT-877 and PTX more potently attenuated the formation of metastatic nodes and accumulation of ascitic fluid. CONCLUSION: These results suggest that BBT-877 can be combined with conventional anticancer drugs for the treatment of patients with recurrent or drug-resistant EOC.

Transplantation of adipose tissue-derived microvascular fragments promotes therapy of critical limb ischemia.

BACKGROUND: Adipose tissue-derived microvascular fragments are functional vessel segments derived from arterioles, capillaries, and veins. Microvascular fragments can be used as vascularization units in regenerative medicine and tissue engineering containing microvascular networks. However, the in vivo therapeutic and vascularization properties of human microvascular fragments have not been investigated. METHODS: In this study, we isolated microvascular fragments, stromal vascular fractions, and mesenchymal stem cells from human lipoaspirate and studied their therapeutic efficacy and in vivo vasculogenic activity in a murine model of hindlimb ischemia. In addition, in vivo angiogenic activity and engraftment of microvascular fragments into blood vessels were measured using Matrigel plug assay. RESULTS: Both microvascular fragments and stromal vascular fractions contain not only mesenchymal stem cells but also endothelial progenitor cells. In a Matrigel plug assay, microvascular fragments increased the number of blood vessels containing red blood cells more than mesenchymal stem cells and stromal vascular fractions did. The engraftment of the microvascular fragments transplanted in blood vessels within the Matrigel plug significantly increased compared to the engraftment of mesenchymal stem cells and stromal vascular fractions. Moreover, intramuscular injection of microvascular fragments markedly increased blood flow in the ischemic hindlimbs and alleviated tissue necrosis compared to that of mesenchymal stem cells or stromal vascular fractions. Furthermore, transplanted microvascular fragments formed new blood vessels in ischemic limbs. CONCLUSIONS: These results suggest that microvascular fragments show improved engraftment efficiency and vasculogenic activity in vivo and are highly useful for treating ischemic diseases and in tissue engineering. Adipose tissue-derived microvascular fragments are vascularization units in regenerative medicine and tissue engineering containing microvascular networks. Intramuscular injection of microvascular fragments markedly increased blood flow in the ischemic hindlimbs and alleviated tissue necrosis. The present study suggests that microvascular fragments show improved engraftment efficiency and vasculogenic activity in vivo and are highly useful for treating ischemic diseases and in tissue engineering.

CD109 Promotes Drug Resistance in A2780 Ovarian Cancer Cells by Regulating the STAT3-NOTCH1 Signaling Axis.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy owing to relapse caused by resistance to chemotherapy. We previously reported that cluster of differentiation 109 (CD109) expression is positively correlated with poor prognosis and chemoresistance in patients with EOC. To further explore the role of CD109 in EOC, we explored the signaling mechanism of CD109-induced drug resistance. We found that CD109 expression was upregulated in doxorubicin-resistant EOC cells (A2780-R) compared with that in their parental cells. In EOC cells (A2780 and A2780-R), the expression level of CD109 was positively correlated with the expression level of ATP-binding cassette (ABC) transporters, such as ABCB1 and ABCG2, and paclitaxel (PTX) resistance. Using a xenograft mouse model, it was confirmed that PTX administration in xenografts of CD109-silenced A2780-R cells significantly attenuated in vivo tumor growth. The treatment of CD109-overexpressed A2780 cells with cryptotanshinone (CPT), a signal transducer and activator of transcription 3 (STAT3) inhibitor, inhibited the CD109 overexpression-induced activation of STAT3 and neurogenic locus notch homolog protein 1 (NOTCH1), suggesting a STAT3-NOTCH1 signaling axis. The combined treatment of CD109-overexpressed A2780 cells with CPT and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), a NOTCH inhibitor, markedly abrogated PTX resistance. These results suggest that CD109 plays a key role in the acquisition of drug resistance by activating the STAT3-NOTCH1 signaling axis in patients with EOC.

Mesenchymal stem cell spheroids alleviate neuropathic pain by modulating chronic inflammatory response genes.

Chronic neuropathic pain is caused by dysfunction of the peripheral nerves associated with the somatosensory system. Mesenchymal stem cells (MSCs) have attracted attention as promising cell therapeutics for chronic pain; however, their clinical application has been hampered by the poor in vivo survival and low therapeutic efficacy of transplanted cells. Increasing evidence suggests enhanced therapeutic efficacy of spheroids formed by three-dimensional culture of MSCs. In the present study, we established a neuropathic pain murine model by inducing a chronic constriction injury through ligation of the right sciatic nerve and measured the therapeutic effects and survival efficacy of spheroids. Monolayer-cultured and spheroids were transplanted into the gastrocnemius muscle close to the damaged sciatic nerve. Transplantation of spheroids alleviated chronic pain more potently and exhibited prolonged in vivo survival compared to monolayer-cultured cells. Moreover, spheroids significantly reduced macrophage infiltration into the injured tissues. Interestingly, the expression of mouse-origin genes associated with inflammatory responses, Ccl11/Eotaxin, interleukin 1A, tumor necrosis factor B, and tumor necrosis factor, was significantly attenuated by the administration of spheroids compared to that of monolayer. These results suggest that MSC spheroids exhibit enhanced in vivo survival after cell transplantation and reduced the host inflammatory response through the regulation of main chronic inflammatory response-related genes.

Inhibition of MEK-ERK pathway enhances oncolytic vaccinia virus replication in doxorubicin-resistant ovarian cancer.

Oncolytic vaccinia virus (OVV) has been reported to induce cell death in various types of cancer; however, the oncolytic activity of OVV in drug-resistant ovarian cancer remains limited. In the present study, we established doxorubicin-resistant ovarian cancer cells (A2780-R) from the A2780 human ovarian cancer cell line. Both A2780 and A2780-R cells were infected with OVV to explore its anticancer effects. Interestingly, OVV-infected A2780-R cells showed reduced viral replication and cell death compared with A2780 cells, suggesting their resistance against OVV-induced oncolysis; to understand the mechanism underlying this resistance, we explored the involvement of protein kinases. Among protein kinase inhibitors, PD0325901, an MEK inhibitor, significantly augmented OVV replication and cell death in A2780-R cells. PD0325901 treatment increased the phosphorylation of STAT3 in A2780-R cells. Moreover, cryptotanshinone, a STAT3 inhibitor, abrogated PD0325901-stimulated OVV replication. Furthermore, trametinib, a clinically approved MEK inhibitor, increased OVV replication in A2780-R cells. Transcriptomic analysis showed that the MEK inhibitor promoted OVV replication via increasing STAT3 activation and downregulating the cytosolic DNA-sensing pathway. Combined treatment with OVV and trametinib attenuated A2780-R xenograft tumor growth. These results suggest that pharmacological inhibition of MEK reinforces the oncolytic efficacy of OVV in drug-resistant ovarian cancer.

Yolk-Shell-Type Gold Nanoaggregates for Chemo- and Photothermal Combination Therapy for Drug-Resistant Cancers.

Epithelial ovarian cancer is a gynecological cancer with the highest mortality rate, and it exhibits resistance to conventional drugs. Gold nanospheres have gained increasing attention over the years as photothermal therapeutic nanoparticles, owing to their excellent biocompatibility, chemical stability, and ease of synthesis; however, their practical application has been hampered by their low colloidal stability and photothermal effects. In the present study, we developed a yolk-shell-structured silica nanocapsule encapsulating aggregated gold nanospheres (aAuYSs) and examined the photothermal effects of aAuYSs on cell death in drug-resistant ovarian cancers both in vitro and in vivo. The aAuYSs were synthesized using stepwise silica seed synthesis, surface amino functionalization, gold nanosphere decoration, mesoporous organosilica coating, and selective etching of the silica template. Gold nanospheres were agglomerated in the confined silica interior of aAuYSs, resulting in the red-shifting of absorbance and enhancement of the photothermal effect under 808 nm laser irradiation. The efficiency of photothermal therapy was first evaluated by inducing aAuYS-mediated cell death in A2780 ovarian cancer cells, which were cultured in a two-dimensional culture and a three-dimensional spheroid culture. We observed that photothermal therapy using aAuYSs together with doxorubicin treatment synergistically induced the cell death of doxorubicin-resistant A2780 cancer cells in vitro. Furthermore, this type of combinatorial treatment with photothermal therapy and doxorubicin synergistically inhibited the in vivo tumor growth of doxorubicin-resistant A2780 cancer cells in a xenograft transplantation model. These results suggest that photothermal therapy using aAuYSs is highly effective in the treatment of drug-resistant cancers.

TRIB2 Stimulates Cancer Stem-Like Properties through Activating the AKT-GSK3ß-ß-Catenin Signaling Axis.

Tribbles homolog 2 (TRIB2) is implicated in tumorigenesis and drug resistance in various types of cancers. However, the role of TRIB2 in the regulation of tumorigenesis and drug resistance of cancer stem cells (CSCs) is still elusive. In the present study, we showed increased expression of TRIB2 in spheroid-forming and aldehyde dehydrogenase-positive CSC populations of A2780 epithelial ovarian cancer cells. Short hairpin RNA-mediated silencing of TRIB2 expression attenuates the spheroid-forming, migratory, tumorigenic, and drug-resistant properties of A2780 cells, whereas overexpression of TRIB2 increases the CSC-like characteristics. TRIB2 overexpression induced GSK3ß inactivation by augmenting AKT-dependent phosphorylation of GSK3ß at Ser9, followed by increasing ß-catenin level via reducing the GSK3ß-mediated phosphorylation of ß-catenin. Treatment of TRIB2-ovexpressed A2780 cells with the phosphoinositide-3-kinase inhibitor LY294002 abrogated TRIB2-stimulated proliferation, migration, drug resistance of A2780 cells. These results suggest a critical role for TRIB2 in the regulation of CSC-like properties by increasing the stability of ß-catenin protein via the AKT-GSK3ß-dependent pathways.

Therapeutic Strategies for Targeting Ovarian Cancer Stem Cells.

Ovarian cancer is a fatal gynecological malignancy. Although first-line chemotherapy and surgical operation are effective treatments for ovarian cancer, its clinical management remains a challenge owing to intrinsic or acquired drug resistance and relapse at local or distal lesions. Cancer stem cells (CSCs) are a small subpopulation of cells inside tumor tissues, and they can self-renew and differentiate. CSCs are responsible for the cancer malignancy involved in relapses as well as resistance to chemotherapy and radiation. These malignant properties of CSCs are regulated by cell surface receptors and intracellular pluripotency-associated factors triggered by internal or external stimuli from the tumor microenvironment. The malignancy of CSCs can be attenuated by individual or combined restraining of cell surface receptors and intracellular pluripotency-associated factors. Therefore, targeted therapy against CSCs is a feasible therapeutic tool against ovarian cancer. In this paper, we review the prominent roles of cell surface receptors and intracellular pluripotency-associated factors in mediating the stemness and malignancy of ovarian CSCs.

CD166 promotes the cancer stem-like properties of primary epithelial ovarian cancer cells.

Cancer stem cells (CSCs) or tumor-initiating cells are thought to play critical roles in tumorigenesis, metastasis, drug resistance, and tumor recurrence. For the diagnosis and targeted therapy of CSCs, the molecular identity of biomarkers or therapeutic targets for CSCs needs to be clarified. In this study, we identified CD166 as a novel marker expressed in the sphereforming CSC population of A2780 epithelial ovarian cancer cells and primary ovarian cancer cells. The CD166+ cells isolated from A2780 cells and primary ovarian cancer cells highly expressed CSC markers, including ALDH1a1, OCT4, and SOX2, and ABC transporters, which are implicated in the drug resistance of CSCs. The CD166+ cells exhibited enhanced CSC-like properties, such as increased sphere-forming ability, cell migration and adhesion abilities, resistance to conventional anticancer drugs, and high tumorigenic potential in a xenograft mouse model. Knockdown of CD166 expression in the sphereforming ovarian CSCs abrogated their CSC-like properties. Moreover, silencing of CD166 expression in the sphere-forming CSCs suppressed the phosphorylation of focal adhesion kinase, paxillin, and SRC. These results suggest that CD166 plays a key role in the regulation of CSC-like properties and focal adhesion kinase signaling in ovarian cancer. [BMB Reports 2020; 53(12): 622-627].

Poly(N-isopropylacrylamide)-b-Poly(L-lysine)-b-Poly(L-histidine) Triblock Amphiphilic Copolymer Nanomicelles for Dual-Responsive Anticancer Drug Delivery.

A series of ABC triblock poly(N-isopropylacrylamide)75-block-poly(L-lysine)35-block-poly(L-histidine)n (p(NIPAM)75-b-p(Lys)35-b-p(His)N) (N = 35,50,75,100) copolymer bio-conjugates were prepared by combining reversible addition-fragmentation chain transfer polymerization and fast ring-opening polymerization of N-carboxyanhydride a-amino acid using 1,3-dicyclohexylimidazolium hydrogen carbonate as a catalyst. All the resulting triblock copolymers self-assembled into spherical micellar aggregates in aqueous solution, irrespective of the chain length of the histidine block. The micellar aggregates encapsulated the anticancer drug doxorubicin (Dox) and exhibited high drug loading efficiency. Temperature and pH stimuli were applied to investigate the controlled release of Dox. The non-cytotoxic nature of the polymers was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cellular uptake of the Dox-loaded micelles revealed that the micelles successfully release Dox in cancer cells in response to pH- and temperature-induced morphological change. In-vitro studies further confirmed that the Dox-loaded triblock copolymer micelle is an excellent platform for drug delivery.

Multi-stimuli-responsive nanomicelles fabricated using synthetic polymer polylysine conjugates for tumor microenvironment dependent drug delivery.

A series of multi-stimuli-responsive poly(N-isopropylacrylamide)30-SS-block-poly(L-lysine)30-block-poly(caprolactone)n (p(NIPAM)30-SS-b-p(Lys)30-b-p(CL)n) (n = 50, 75, 100, 125) triblock copolymers have been synthesized by combining reversible addition-fragmentation chain transfer polymerization of NIPAM, organo-catalyzed ring-opening polymerization (ROP) of Z-lysine N-carboxyanhydride and metal-catalyzed ROP of CL with an azide-alkyne click reaction. The pH-responsive p(Lys) and temperature-responsive p(NIPAM) blocks are tethered by a redox-responsive disulfide linker and biodegradable p(CL) blocks with different lengths are also combined to tune the lower critical solution temperature and drug loading capacity of the resulting polymers. Highly uniform micelles with ∼200 nm size were fabricated by the self-assembly of the resultant copolymers in the presence of doxorubicin (Dox) with a high Dox encapsulation efficiency of around 50%. The combination of the enhanced permeability and retention effect with pH-, temperature- and redox-sensitive tumor microenvironment-responsive drug delivery of the nanomicelles endows them with cell internalization capability for the successful antitumor efficiency. Interestingly, this multi-stimuli-responsive platform makes a distinction from the conventional block copolymer systems by demonstrating fascinating tumor targeting without utilizing any targeting moiety. Thus, the easily accessible multi-stimuli-responsive triblock copolymer can be a promising theranostic system for intracellular drug delivery.

Enhanced Photoinduced Carrier Generation Efficiency through Surface Band Bending in Topological Insulator Bi2Se3 Thin Films by the Oxidized Layer.

Topological insulators (TIs) have become popular in the field of optoelectronic devices because of their broadband and high-sensitivity properties, which are attributed to the narrow band gap of the bulk state and high mobility of the Dirac surface state. Although perfectly grown TIs are known to exhibit strong stability against oxidation, in most cases, the existence of vacancy defects in TIs reacts to air and the characteristics of TIs is affected by oxidation. Therefore, changes in the band structure and electrical characteristics by oxidation should be considered. A significant change occurs because of the oxidation; however, the dependence of the photoresponse of TIs on oxidation has not been studied in detail. In this study, the photoresponsivity of oxidized Bi2Se3 films is enhanced, rather than degraded, after oxidation in air for 24 h, resulting in a maximum responsivity of 140 mA W-1. This responsivity is substantially higher than previously reported values for Bi2Se3. Furthermore, a change in the photoresponse time of Bi2Se3 due to air exposure is systematically observed. Based on variations in the Fermi level and work function, using photoelectron spectroscopy, it is confirmed that the responsivity is improved from the junction effect of the Bi-based surface oxidized layer.

Facile and scalable synthesis of topologically nanoengineered polypeptides with excellent antimicrobial activities.

A facile and scalable strategy for the quick library synthesis of linear-, hinged-, star-, and cyclic-polypeptides with broad-spectrum antimicrobial activity has been reported. The topologically nanoengineered polypeptides show superior antimicrobial activity against Gram-positive and Gram-negative bacteria and low toxicity, allowing screening of architectural polypeptides as mimics of host defense peptides for antimicrobials.

P-N Junction Diode Using Plasma Boron-Doped Black Phosphorus for High-Performance Photovoltaic Devices.

This study used a spatially controlled boron-doping technique that enables a p-n junction diode to be realized within a single 2D black phosphorus (BP) nanosheet for high-performance photovoltaic application. The reliability of the BP surface and state-of-the-art 2D p-n heterostructure's gated junctions was obtained using the controllable pulsed-plasma process technique. Chemical and structural analyses of the boron-doped BP were performed using X-ray photoelectron spectroscopy, transmission electron microscopy, and first-principles density functional theory (DFT) calculations, and the electrical characteristics of a field-effect transistor based on the p-n heterostructure were determined. The incorporated boron generated high electron density at the BP surface. The electron mobility of BP was significantly enhanced to ∼265 cm2/V·s for the top gating mode, indicating greatly improved electron transport behavior. Ultraviolet photoelectron spectroscopy and DFT characterizations revealed the occurrence of significant surface charge transfer in the BP. Moreover, the pulsed-plasma boron-doped BP p-n junction devices exhibited high-efficiency photodetection behavior (rise time: 1.2 ms and responsivity: 11.3 mA/W at Vg = 0 V). This study's findings on the tunable nature of the surface-transfer doping scheme reveal that BP is a promising candidate for optoelectronic devices and advanced complementary logic electronics.

Interface engineering for a stable chemical structure of oxidized-black phosphorus via self-reduction in AlOx atomic layer deposition.

We evaluated the change in the chemical structure between dielectrics (AlOx and HfOx) grown by atomic layer deposition (ALD) and oxidized black phosphorus (BP), as a function of air exposure time. Chemical and structural analyses of the oxidized phosphorus species (PxOy) were performed using atomic force microscopy, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscopy, first-principles density functional theory calculations, and the electrical characteristics of field-effect transistors (FETs). Based on the combined experiments and theoretical investigations, we clearly show that oxidized phosphorus species (PxOy, until exposed for 24 h) are significantly decreased (self-reduction) during the ALD of AlOx. In particular, the field effect characteristics of a FET device based on Al2O3/AlOx/oxidized BP improved significantly with enhanced electrical properties, a mobility of ∼253 cm2 V-1 s-1 and an on-off ratio of ∼105, compared to those of HfO2/HfOx/oxidized BP with a mobility of ∼97 cm2 V-1 s-1 and an on-off ratio of ∼103-104. These distinct differences result from a significantly decreased interface trap density (Dit ∼ 1011 cm-2 eV-1) and subthreshold gate swing (SS ∼ 270 mV dec-1) in the BP device caused by the formation of stable energy states at the AlOx/oxidized BP interface, even with BP oxidized by air exposure.

TRRAP stimulates the tumorigenic potential of ovarian cancer stem cells.

Ovarian cancer is the most fatal gynecological malignancy in women and identification of new therapeutic targets is essential for the continued development of therapy for ovarian cancer. TRRAP (transformation/transcription domain-associated protein) is an adaptor protein and a component of histone acetyltransferase complex. The present study was undertaken to investigate the roles played by TRRAP in the proliferation and tumorigenicity of ovarian cancer stem cells. TRRAP expression was found to be up-regulated in the sphere cultures of A2780 ovarian cancer cells. Knockdown of TRRAP significantly decreased cell proliferation and the number of A2780 spheroids. In addition, TRRAP knockdown induced cell cycle arrest and increased apoptotic percentages of A2780 sphere cells. Notably, the mRNA levels of stemness-associated markers, that is, OCT4, SOX2, and NANOG, were suppressed in TRRAP-silenced A2780 sphere cells. In addition, TRRAP overexpression increased the mRNA level of NANOG and the transcriptional activity of NANOG promoter in these cells. Furthermore, TRRAP knockdown significantly reduced tumor growth in a murine xenograft transplantation model. Taken together, the findings of the present study suggest that TRRAP plays an important role in the regulation of the proliferation and stemness of ovarian cancer stem cells. [BMB Reports 2018; 51(10): 515-520].

Role of Krüppel-Like Factor 4 in the Maintenance of Chemoresistance of Anaplastic Thyroid Cancer.

BACKGROUND: Anaplastic thyroid cancer (ATC) has a very poor prognosis due to its aggressive nature and resistance to conventional treatment. Radiotherapy and chemotherapy are not fully effective because of the undifferentiated phenotype and enhanced drug resistance of ATC. The objective of this study was to evaluate the involvement of Krüppel-like factor 4 (KLF4), a stemness-associated transcription factor, in the undifferentiated phenotype and drug resistance of ATC. METHODS: ATC cells were compared to papillary thyroid cancer cells in drug resistance and gene expression. The effects of KLF4 knockdown in ATC cells on in vitro and in vivo drug resistance were measured. The effects of KLF4 overexpression and knockdown on ABC transporter activity were determined. RESULTS: ATC cells, such as HTH83, 8505C, and SW1736, exhibited higher resistance to the anticancer drug paclitaxel and higher expression of KLF4 than TPC-1 papillary thyroid cancer cells. Knockdown of KLF4 expression in ATC cells increased the expression of the thyroid-specific differentiation genes, such as thyrotropin receptor, thyroid peroxidase, thyroglobulin, and sodium-iodide symporter. Knockdown of KLF4 expression in ATC cells decreased the resistance to doxorubicin and paclitaxel, and reduced ABC transporter expression. Luciferase reporter assay results showed that KLF4 overexpression increased ABCG2 promoter activity, which was abolished by KLF4 knockdown. A tumorigenicity assay showed that the combination of paclitaxel treatment and KLF4 knockdown significantly decreased tumor mass originated from HTH83 cells in mice. CONCLUSIONS: ATC cells show high expression of KLF4, and KLF4 expression is necessary for maintaining the undifferentiated phenotype and drug resistance in vitro and in vivo. The present study identifies KLF4 as a potential therapeutic target for eliminating ATC cells.

Al2O3 Passivation Effect in HfO2·Al2O3 Laminate Structures Grown on InP Substrates.

The passivation effect of an Al2O3 layer on the electrical properties was investigated in HfO2-Al2O3 laminate structures grown on indium phosphide (InP) substrate by atomic-layer deposition. The chemical state obtained using high-resolution X-ray photoelectron spectroscopy showed that interfacial reactions were dependent on the presence of the Al2O3 passivation layer and its sequence in the HfO2-Al2O3 laminate structures. Because of the interfacial reaction, the Al2O3/HfO2/Al2O3 structure showed the best electrical characteristics. The top Al2O3 layer suppressed the interdiffusion of oxidizing species into the HfO2 films, whereas the bottom Al2O3 layer blocked the outdiffusion of In and P atoms. As a result, the formation of In-O bonds was more effectively suppressed in the Al2O3/HfO2/Al2O3/InP structure than that in the HfO2-on-InP system. Moreover, conductance data revealed that the Al2O3 layer on InP reduces the midgap traps to 2.6 × 1012 eV-1 cm-2 (compared to that of HfO2/InP, that is, 5.4 × 1012 eV-1 cm-2). The suppression of gap states caused by the outdiffusion of In atoms significantly controls the degradation of capacitors caused by leakage current through the stacked oxide layers.

Controlling the defects and transition layer in SiO2 films grown on 4H-SiC via direct plasma-assisted oxidation.

The structural stability and electrical performance of SiO2 grown on SiC via direct plasma-assisted oxidation were investigated. To investigate the changes in the electronic structure and electrical characteristics caused by the interfacial reaction between the SiO2 film (thickness ~5 nm) and SiC, X-ray photoelectron spectroscopy (XPS), X-ray absorption spectroscopy (XAS), density functional theory (DFT) calculations, and electrical measurements were performed. The SiO2 films grown via direct plasma-assisted oxidation at room temperature for 300s exhibited significantly decreased concentrations of silicon oxycarbides (SiOxCy) in the transition layer compared to that of conventionally grown (i.e., thermally grown) SiO2 films. Moreover, the plasma-assisted SiO2 films exhibited enhanced electrical characteristics, such as reduced frequency dispersion, hysteresis, and interface trap density (Dit ≈ 1011 cm-2 · eV-1). In particular, stress induced leakage current (SILC) characteristics showed that the generation of defect states can be dramatically suppressed in metal oxide semiconductor (MOS) structures with plasma-assisted oxide layer due to the formation of stable Si-O bonds and the reduced concentrations of SiOxCy species defect states in the transition layer. That is, energetically stable interfacial states of high quality SiO2 on SiC can be obtained by the controlling the formation of SiOxCy through the highly reactive direct plasma-assisted oxidation process.

Crucial role of HMGA1 in the self-renewal and drug resistance of ovarian cancer stem cells.

Cancer stem cells are a subpopulation of cancer cells characterized by self-renewal ability, tumorigenesis and drug resistance. The aim of this study was to investigate the role of HMGA1, a chromatin remodeling factor abundantly expressed in many different cancers, in the regulation of cancer stem cells in ovarian cancer. Spheroid-forming cancer stem cells were isolated from A2780, SKOV3 and PA1 ovarian cancer cells by three-dimensional spheroid culture. Elevated expression of HMGA1 was observed in spheroid cells along with increased expression of stemness-related genes, such as SOX2, KLF4, ALDH, ABCB1 and ABCG2. Furthermore, spheroid A2780 cells, compared with adherent cells, showed higher resistance to chemotherapeutic agents such as paclitaxel and doxorubicin. HMGA1 knockdown in spheroid cells reduced the proliferative advantage and spheroid-forming efficiency of the cells and the expression of stemness-related genes. HMGA1 overexpression in adherent A2780 cells increased cancer stem cell properties, including proliferation, spheroid-forming efficiency and the expression of stemness-related genes. In addition, HMGA1 regulated ABCG2 promoter activity through HMGA1-binding sites. Knockdown of HMGA1 in spheroid cells reduced resistance to chemotherapeutic agents, whereas the overexpression of HMGA1 in adherent ovarian cancer cells increased resistance to chemotherapeutic agents in vitro. Furthermore, HMGA1-overexpressing A2780 cells showed a significant survival advantage after chemotherapeutic agent treatment in a xenograft tumorigenicity assay. Together, our results provide novel insights regarding the critical role of HMGA1 in the regulation of the cancer stem cell characteristics of ovarian cancer cells, thus suggesting that HMGA1 may be an important target in the development of therapeutics for ovarian cancer patients.