Forming-Free, Low-Voltage, and High-Speed Resistive Switching in Ag/Oxygen-Deficient Vanadium Oxide(VOx)/Pt Device through Two-Step Resistance Change by Ag Filament Formation.

Forming-free, low-voltage, and high-speed resistive switching is demonstrated in an Ag/oxygen-deficient vanadium oxide (VOx)/Pt device via the facilitated formation and rupture of Ag filaments. Direct current (DC) voltage sweep measurements exhibit forming-free switching from a high-resistance state (HRS) to a low-resistance state (LRS), called SET, at an average VSET of +0.23 V. The reverse RESET transition occurs at an average VRESET of -0.07 V with a low RESET current of <1 mA. Reversible switching operations are stable with an HRS/LRS resistance ratio >103 during repeated measurements for thousands of cycles. In pulse measurements, switching occurs within 100 ns at an amplitude of +1.5 V. Notably, a two-step resistance change is observed in the SET operation, where the resistance first partially decreases due to Ag+ ion accumulation in VOx and then further decreases to the LRS after hundreds of nanoseconds upon complete filament formation. The VOx layer deposited to be mostly amorphous with oxygen deficiency from V2O5 has abundant vacancies and expedites Ag+ ion migration, thus realizing forming-free, high-speed, and low-voltage switching. These characteristics of the facilitated Ag filament formation using the substoichiometric VOx layer are highly beneficial for use as stand-alone nonvolatile memory and in-memory computing elements.

Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation.

BACKGROUND: Coronary artery bypass graft (CABG) is generally used to treat complex coronary artery disease. Treatment success is affected by neointimal hyperplasia (NIH) of graft and anastomotic sites. Although sirolimus and rosuvastatin individually inhibit NIH progression, the efficacy of combination treatment remains unknown. METHODS: We identified cross-targets associated with CABG, sirolimus, and rosuvastatin by using databases including DisGeNET and GeneCards. GO and KEGG pathway enrichment analyses were conducted using R studio, and target proteins were mapped in PPI networks using Metascape and Cytoscape. For in vivo validation, we established a balloon-injured rabbit model by inducing NIH and applied a localized perivascular drug delivery device containing sirolimus and rosuvastatin. The outcomes were evaluated at 1, 2, and 4 weeks post-surgery. RESULTS: We identified 115 shared targets between sirolimus and CABG among databases, 23 between rosuvastatin and CABG, and 96 among all three. TNF, AKT1, and MMP9 were identified as shared targets. Network pharmacology predicted the stages of NIH progression and the corresponding signaling pathways linked to sirolimus (acute stage, IL6/STAT3 signaling) and rosuvastatin (chronic stage, Akt/MMP9 signaling). In vivo experiments demonstrated that the combination of sirolimus and rosuvastatin significantly suppressed NIH progression. This combination treatment also markedly decreased the expression of inflammation and Akt signaling pathway-related proteins, which was consistent with the predictions from network pharmacology analysis. CONCLUSIONS: Sirolimus and rosuvastatin inhibited pro-inflammatory cytokine production during the acute stage and regulated Akt/mTOR/NF-κB/STAT3 signaling in the chronic stage of NIH progression. These potential synergistic mechanisms may optimize treatment strategies to improve long-term patency after CABG.

Nanoscale Vertical Resolution in Optical Printing of Inorganic Nanoparticles.

Direct optical printing of functional inorganics shows tremendous potential as it enables the creation of intricate two-dimensional (2D) patterns and affordable design and production of various devices. Although there have been recent advancements in printing processes using short-wavelength light or pulsed lasers, the precise control of the vertical thickness in printed 3D structures has received little attention. This control is vital to the diverse functionalities of inorganic thin films and their devices, as they rely heavily on their thicknesses. This lack of research is attributed to the technical intricacy and complexity involved in the lithographic processes. Herein, we present a generalized optical 3D printing process for inorganic nanoparticles using maskless digital light processing. We develop a range of photocurable inorganic nanoparticle inks encompassing metals, semiconductors, and oxides, combined with photolinkable ligands and photoacid generators, enabling the direct solidification of nanoparticles in the ink medium. Our process creates complex and large-area patterns with a vertical resolution of ∼50 nm, producing 50-nm-thick 2D films and several micrometer-thick 3D architectures with no layer height difference via layer-by-layer deposition. Through fabrication and operation of multilayered switching devices with Au electrodes and Ag-organic resistive layers, the feasibility of our process for cost-effective manufacturing of multilayered devices is demonstrated.

Effect of sequential release of sirolimus and rosuvastatin using silk fibroin microneedle to prevent intimal hyperplasia.

Intimal hyperplasia (IH) is a major cause of vascular restenosis after bypass surgery, which progresses as a series of processes from the acute to chronic stage in response to endothelial damage during bypass grafting. A strategic localized drug delivery system that reflects the pathophysiology of IH and minimizes systemic side effects is necessary. In this study, the sequential release of sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, and statin, an HMG-COA inhibitor, was realized as a silk fibroin-based microneedle device in vivo. The released sirolimus in the acute stage reduced neointima (NI) and vascular fibrosis through mTOR inhibition. Furthermore, rosuvastatin, which was continuously released from the acute to chronic stage, reduced vascular stiffness and apoptosis through the inactivation of Yes-associated protein (YAP). The sequential release of sirolimus and rosuvastatin confirmed the synergistic treatment effects on vascular inflammation, VSMC proliferation, and ECM degradation remodeling through the inhibition of transforming growth factor (TGF)-beta/NF-κB pathway. These results demonstrate the therapeutic effect on preventing restenosis with sufficient vascular elasticity and significantly reduced IH in response to endothelial damage. Therefore, this study suggests a promising strategy for treating coronary artery disease through localized drug delivery of customized drug combinations.

Sirolimus-Embedded Silk Microneedle Wrap to Prevent Neointimal Hyperplasia in Vein Graft Model.

We investigated the role of a sirolimus-embedded silk microneedle (MN) wrap as an external vascular device for drug delivery efficacy, inhibition of neointimal hyperplasia, and vascular remodeling. Using dogs, a vein graft model was developed to interpose the carotid or femoral artery with the jugular or femoral vein. The control group contained four dogs with only interposed grafts; the intervention group contained four dogs with vein grafts in which sirolimus-embedded silk-MN wraps were applied. After 12-weeks post-implantation, 15 vein grafts in each group were explanted and analyzed. Vein grafts applied with the rhodamine B-embedded silk-MN wrap showed far higher fluorescent signals than those without the wrap. The diameter of vein grafts in the intervention group decreased or remained stable without dilatation; however, it increased in the control group. The intervention group had femoral vein grafts with a significantly lower mean neointima-to-media ratio, and had vein grafts with an intima layer showing a significantly lower collagen density ratio than the control group. In conclusion, sirolimus-embedded silk-MN wrap in a vein graft model successfully delivered the drug to the intimal layer of the vein grafts. It prevented vein graft dilatation, avoiding shear stress and decreasing wall tension, and it inhibited neointimal hyperplasia.

Electroforming-free threshold switching of NbO x -based selector devices by controlling conducting phases in the NbO x layer for the application to crossbar array architectures.

Bipolar threshold switching characteristics, featuring volatile transition between the high-resistance state (HRS) at lower voltage than threshold voltage (V th) and the low-resistance state (LRS) at higher voltage irrespective of the voltage polarity, are investigated in the Nb(O)/NbO x /Nb(O) devices with respect to deposition and post-annealing conditions of NbO x layers. The device with NbO x deposited by reactive sputtering with 12% of O2 gas mixed in Ar shows threshold switching behaviors after electroforming operation at around +4 V of forming voltage (V f). On the other hand, electroforming-free threshold switching is achieved from the device with NbO x deposited in the reduced fraction of 7% of O2 gas and subsequently annealed at 250 °C in vacuum, thanks to the increase of the amount of conducting phases within the NbO x layer. Threshold switching is thought to be driven by the formation of a temporally percolated filament composed of conducting NbO and NbO2 phases in the NbO x layer, which were formed as a result of the interaction with Nb electrodes such as oxygen ion migration either by annealing or electrical biasing. The presence of a substantial amount of oxygen in the Nb electrodes up to ∼40 at%, named Nb(O) herein, would alleviate excessive migration of oxygen and consequent overgrowth of the filament during operation, thus enabling reliable threshold switching. These results demonstrate a viable route to realize electroforming-free threshold switching in the Nb(O)/NbO x /Nb(O) devices by controlling the contents of conducting phases in the NbO x layer for the application to selector devices in high-density crossbar memory and synapse array architectures.

Time-dependent pathobiological and physiological changes of implanted vein grafts in a canine model.

Although autologous vein grafting is essential, the high vein failure rate and specific clinical interventions are not clear, so a potential treatment is critically needed; thus, complex analyses of the relationship between pathobiological and physiological processes in preclinical are essential. The interposition of the femoral vein was performed in a canine model. Maximized expansion and velocity were measured at 8 weeks post-implantation, and a relative decrease was observed at 12 weeks. However, NI formation and NI/Media ratio significantly increased time dependently, and differences between the mechanical properties were observed. Additionally, RhoA-mediated TNF-α induced by rapid structural changes and high shear stress was confirmed. After adaptation to the arterial environment, vascular remodeling occurred by SMC proliferation and differentiation, apoptosis and autophagy were induced through YAP activity without vasodilation and RhoA activity. Our results show that understanding pathobiological processes in which time-dependent physiological changes contribute to vein failure can lead to a potential strategy. The implanted vein graft within the arterial environment undergoes pathobiological processes through RhoA and YAP activity, leading to pathophysiological changes.

Current status and future perspective of external herbal dispensaries preparing traditional herbal medicine in South Korea: the first National-Wide Survey results.

BACKGROUND: An external herbal dispensary (EHD) is a type of pharmacy that provides various types of personalized herbal medicines (PHMs) to other traditional Korean medicine (TKM) institutions. Such dispensaries were legalized by the Ministry of Health and Welfare (MoHW) in 2008 in South Korea. The purpose of this study is to understand the current status of the EHD facilities and their quality controls and compare them with the good manufacture practice (GMP) guidelines to contribute to the establishment of the safety and quality control criteria for PHMs. METHODS: We contacted 107 EHD representatives or people in charge of the preparation of PHMs (TKM pharmacists) and invited them to complete a survey questionnaire; of the total, 81 responded. The survey questionnaire was developed in 3 stages: drafting, revision by external experts, and final editing. It consisted of 20 questions covering 3 sections: basic characteristics of EHDs, facility, and quality control. The survey was hosted online from December 2017 to January 2018 as guided by the MoHW. RESULTS: The completion rate was 75.7% (n = 81). In terms of facilities, the five facilities (water supply, manufacture, pest control, hygiene management and warehousing) that corresponded to the legal requirements of EHD were mostly equipped, but the types of facilities and equipment differed. Two facilities (sterilization and cross-contamination that were not legally required for EHD were found to have mostly pharmacopuncture-EHD (P-EHD), but hardly any herbal medicine-EHD (H-EHD). In our findings regarding quality control of non-medicinal herbs, sensory evaluation that included checks for foreign bodies and deterioration were conducted. In terms of the quality control of herbal medicines, residual pesticides and heavy metals tests were performed and for pharmacopuncture, pH, salinity, sterility, and endotoxin tests along with gross examination were performed. In the end, we found that 6 of the 38 standard items as required by the Korea GMP were suitable. CONCLUSIONS: In this study, detailed information for each existing EHD law was determined through a nationwide questionnaire. Moreover, the basis for its reflection in additional legal standards should be introduced so that safe herbal medicine can be prepared in EHDs.

Effect of Roasting and Brewing on the Antioxidant and Antiproliferative Activities of Tartary Buckwheat.

We evaluated the effect of the roasting and brewing conditions of Tartary buckwheat (TB), which is widely used in infusion teas, on its antioxidant and antiproliferative activities in vitro. TB was roasted at 210 °C for 10 min and brewed at a high temperature for a short time (HTST; 85-90 °C, 3 min) or at room temperature for a long time (RTLT; 25-30 °C, 24 h). Roasted TB (RTB) tea brewed at RTLT had the highest total polyphenol content (TPC) and total flavonoid content (TFC) among the four TB teas for different roasting and brewing conditions. Moreover, RTB brewed at RTLT showed the greatest 2,2-diphenyl-1-picrylhydrazyl-, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)-, and alkyl-scavenging activities. The TB tea brewed at RTLT had higher Fe2+-chelating activity than that brewed at HTST, irrespective of roasting. Moreover, RTB tea brewed at RTLT inhibited the proliferation of human pancreatic and breast cancer cells. Overall, RTB-RTLT displayed the largest effect on antioxidant and antiproliferative effects. Finally, rutin was found to possess the most pronounced effect on the antioxidant and antiproliferative activities of the TB teas. These results indicate that the antioxidant and antiproliferative activities of RTB are enhanced by RTLT brewing.

An Immune-Magnetophoretic Device for the Selective and Precise Enrichment of Circulating Tumor Cells from Whole Blood.

Here, we validated the clinical utility of our previously developed microfluidic device, GenoCTC, which is based on bottom magnetophoresis, for the isolation of circulating tumor cells (CTCs) from patient whole blood. GenoCTC allowed 90% purity, 77% separation rate, and 80% recovery of circulating tumor cells at a 90 µL/min flow rate when tested on blood spiked with epithelial cell adhesion molecule (EpCAM)-positive Michigan Cancer Foundation-7 (MCF7) cells. Clinical studies were performed using blood samples from non-small cell lung cancer (NSCLC) patients. Varying numbers (2 to 114) of CTCs were found in each NSCLC patient, and serial assessment of CTCs showed that the CTC count correlated with the clinical progression of the disease. The applicability of GenoCTC to different cell surface biomarkers was also validated in a cholangiocarcinoma patient using anti-EPCAM, anti-vimentin, or anti-tyrosine protein kinase MET (c-MET) antibodies. After EPCAM-, vimentin-, or c-MET-positive cells were isolated, CTCs were identified and enumerated by immunocytochemistry using anti-cytokeratin 18 (CK18) and anti-CD45 antibodies. Furthermore, we checked the protein expression of PDL1 and c-MET in CTCs. A study in a cholangiocarcinoma patient showed that the number of CTCs varied depending on the biomarker used, indicating the importance of using multiple biomarkers for CTC isolation and enumeration.

Spirobifluorene-Based o-Carboranyl Compounds: Insights into the Rotational Effect of Carborane Cages on Photoluminescence.

9,9'-Spirobifluorene-based closo-o-carboranyl (SFC1 and SFC2) compounds and their nido-derivatives (nido-SFC1 and nido-SFC2) were prepared and characterized. The two closo-compounds displayed major absorption bands assignable to π-π* transitions involving the spirobifluorene group, as well as weak intramolecular charge-transfer (ICT) transitions between the o-carboranes and their spirobifluorene moieties. The nido-compounds exhibited slightly blueshifted absorption bands resulting from the absence of the ICT transitions corresponding to the o-carborane moieties due to the anionic character of the nido-o-carboranes. While SFC1 exhibited only high-energy emissions in THF at 298 K (only from locally excited (LE) states assignable to π-π* transitions on the spirobifluorene group), remarkable emissions in the low-energy region were observed in the rigid state such as in THF at 77 K and in the film state. SFC2 displayed intense emissions in the low-energy region in all states. The fact that neither of the nido-derivatives of SFC1 and SFC2 exhibited low-energy emissions and the TD-DFT calculation results of each closo-compound clearly verified that the low-energy emission was based on ICT-based radiative decay. The conformational barriers from each relative energy calculation upon changing the dihedral angles around the o-carborane cages for both compounds confirmed that the rotation of the o-carborane cages and terminal phenyl rings for SFC1 is freer than that for SFC2.

Current Status of Management on Pharmacopuncture in Korea through Introduction of an Accreditation System.

OBJECTIVES: Pharmacopuncture is a new form of acupuncture treatment that injects herbal medicine into acupuncture points. This paper introduces the management status of pharmacopuncture through accreditation, and examines the effect of accreditation on pharmacopuncture management. METHODS: The Accreditation System of External Herbal Dispensaries (EHDs) of traditional Korean medicine clinics announced by the Ministry of Health and Welfare in September 2018 were investigated. RESULTS: The Accreditation System of EHDs assesses and certifies herbal medicine and pharmacopuncture preparations. Regular components for the 'pharmacopuncture' certification consist of nine standards, 30 categories, and 165 items. The nine standards include: herbal dispensary facilities, clean room management, management and organization operation, employee management, document management, continuous quality control, herbal medicine management, management of preparation, and pavement management. CONCLUSION: Through EHD accreditation and certification system, traditional Korean medicine clinics and EHDs can now manage pharmacopuncture medicine quality and promise safe pharmacopuncture treatment for the people.

Changes Over the Fermentation Period in Phenolic Compounds and Antioxidant and Anticancer Activities of Blueberries Fermented by Lactobacillus plantarum.

This study determined the effects of blueberry fermentation by Lactobacillus plantarum on antioxidant and anticancer activities. The fermented blueberries extracted with 80% ethanol (FBE) showed increased superoxide dismutase-like activity, increased scavenging of DPPH and alkyl radicals, and increased antiproliferative activity against human cervical carcinoma HeLa cells by inducing apoptosis. Seven representative phenolic compounds (malvidin 3-O-glucopyranoside, gallic acid, protocatechuic acid, catechol, chlorogenic acid, syringic acid, and epigallocatechin) in FBE were measured by high-performance liquid chromatography at different fermentation times. The content of each phenolic compound in the FBE was dependent on the fermentation period. Protocatechuic acid and catechol levels increased significantly with fermentation time. Of these three major compounds (protocatechuic acid, catechol, and chlorogenic acid), catechol showed the most significant anticancer activity when HeLa cells were treated with each of these three compounds alone or mixed in various ratios. Pearson's product-moment correlation analysis revealed that the increases in antioxidant and anticancer activities following blueberry fermentation were positively correlated with the phenolic acids present in FBE. PRACTICAL APPLICATION: Blueberries fermented with a tannase-producing lactic acid bacteria (LAB), Lactobacillus plantarum showed higher antioxidant activities and antiproliferative activities against human cervical carcinoma HeLa cells than did raw blueberries. L. plantarum fermentation biotransformed blueberry polyphenols into active phenol metabolites with strong antioxidant and antiproliferative activities. Our results suggest that fermented blueberries are rich in phenolic acids, which are a promising source of natural antioxidants and anticancer drugs and can be used as additives in food, pharmaceuticals, and cosmetic preparations.

Nootkatone, an AMPK activator derived from grapefruit, inhibits KRAS downstream pathway and sensitizes non-small-cell lung cancer A549 cells to adriamycin.

BACKGROUND: Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and it is intrinsically resistant to anticancer drugs. Nootkatone (NKT), which is the main fragrant component of grapefruit, has been identified as a bioactive compound with a wide range of beneficial applications. NKT can activate AMP-activated protein kinase (AMPK) in liver and muscle cells, however, little is known about the role of NKT in cancer, particularly its role in NSCLC with high rates of liver kinase B1 (LKB1) and KRAS mutations. PURPOSE: The anti-cancer activities of NKT in NSCLC A549 cells and ADR-resistant A549/ADR cells were investigated and compared to those of metformin, an AMPK activator that is used clinically as an AMPK activator. METHODS: Cell viability, proliferation and NKT sensitization were determined by the MTT assay. Mechanisms of NKT against anti-cancer activities including AMPK activation, cell cycle arrest, and synergistic cytotoxic effect were evaluated by Western blot analysis, and flow cytometry. In in vivo experiments, athymic BALB/c male nude mice were used for experiments. After the successful generation of tumor models through subcutaneous injection of A549/ADR cells, NKT and/or ADR were administered and mice were kept for weekly measurements for up to 7 weeks. The animals were then sacrificed, and the tumors were removed from all animals and weighed. RESULTS: NKT activated AMPK via LKB1-independent and CAMKK2-dependent pathways, leading to inhibition of cell growth and induction of G1 cell arrest. The effect of NKT is comparable but superior to that of metformin, an AMPK activator in clinical use. Importantly, NKT inhibited the activation of oncogenic AKT and ERK proteins, while metformin inhibited AKT but failed to impact ERK, the major oncogenic protein of NSCLC cells with KRAS mutation. The synergistic activity of NKT and ADR was more effective than that of metformin and ADR. In vivo data confirmed synergistic effects of NKT and ADR without systemic side effects. CONCLUSION: We demonstrate for the first time that NKT can sensitize ADR-resistant A549/ADR cells to ADR in vitro and in vivo. Metformin, on the other hand, failed to show any synergistic effect with ADR in A549/ADR cells.

Methanol Extract of Aerial Parts of Pavetta indica L. Enhances the Cytotoxic Effect of Doxorubicin and Induces Radiation Sensitization in MDA-MB-231 Triple-Negative Breast Cancer Cells.

Pavetta indica L. is used in traditional medicine for the treatment of various diseases including hemorrhoids, headache, urinary conditions, ulcerated nose, and dropsy. However, no study has evaluated the anticancer effect of P. indica L. In this study, we found that a methanol extract of the leaves and branches of P. indica L. (MEPI) caused cellcycle arrest at the sub-G1 phase and induced apoptosis, as indicated by the activation of caspase-8, -3, -7, and c-PARP. Western blotting revealed that MEPI significantly reduced the levels of markers of the epithelial-mesenchymal transition, such as Vimentin, Snail, Slug, and matrix metallopeptidase 9. Notably, the expression of multidrug resistance-associated protein 1 in triple negative breast cancer (TNBC) was significantly decreased by MEPI. Moreover, the co-treatment with MEPI and doxorubicin resulted in a synergistic reduction in cell viability. MEPI also induced radiation sensitization of TNBC cells. Gas chromatography-mass spectrometry analysis revealed that 5,6-dehydrokawain (DK) is the major constituent of MEPI. Interestingly, DK exerted significant anti-invasive and anti-metastatic effects. Our results provide a strong rationale for investigating the molecular mechanisms of action of MEPI in TNBC.

Predictors of disclosure management behavior at the end of 1-year follow-up in Korean adults with newly diagnosed epilepsy.

PURPOSE: Epilepsy is a concealable stigmatizing condition. We investigated the factors predicting disclosure management behavior in Korean adults with newly diagnosed epilepsy. METHODS: This longitudinal multicenter study included Korean adults with newly diagnosed epilepsy. Using statistical analyses, we determined at the end of a 1-year follow-up whether Disclosure Management Scale (DMS) scores were predicted by demographic, clinical, and psychosocial variables, including felt stigma, stress coping style, personality traits, social support, and experienced discrimination from society. RESULTS: Of a total of 121 participants, 69% reported that they often or sometimes kept their diagnosis a secret from others and rarely or never talked to others about their epilepsy. The average DMS score was 5.8 (SD=2.9, range 0-11). In univariate analyses, DMS scores were significantly associated with an emotion-focused coping style (r=0.320, p<0.001), social support (r=-0.185, p<0.05), and experienced discrimination (p<0.05). Emotion-focused coping was the only independent predictor of a higher DMS score. Felt stigma, personality traits, and seizure freedom were not related to the DMS score. CONCLUSIONS: Two-thirds of Korean adults with newly diagnosed epilepsy often or sometimes keep their epilepsy a secret. Emotion-focused coping is the most important predictor of concealment of epilepsy diagnosis at the end of a 1-year follow-up, although social support and episodes of experienced discrimination are also associated with disclosure management strategies.

Highly Expressed Integrin-α8 Induces Epithelial to Mesenchymal Transition-Like Features in Multiple Myeloma with Early Relapse.

Despite recent groundbreaking advances in multiple myeloma (MM) treatment, most MM patients ultimately experience relapse, and the relapse biology is not entirely understood. To define altered gene expression in MM relapse, gene expression profiles were examined and compared among 16 MM patients grouped by 12 months progression-free survival (PFS) after autologous stem cell transplantation. To maximize the difference between prognostic groups, patients at each end of the PFS spectrum (the four with the shortest PFS and four with the longest PFS) were chosen for additional analyses. We discovered that integrin-α8 (ITGA8) is highly expressed in MM patients with early relapse. The integrin family is well known to be involved in MM progression; however, the role of integrin-α8 is largely unknown. We functionally overexpressed integrin-α8 in MM cell lines, and surprisingly, stemness features including HIF1α, VEGF, OCT4, and Nanog, as well as epithelial mesenchymal transition (EMT)-related phenotypes, including N-cadherin, Slug, Snail and CXCR4, were induced. These, consequently, enhanced migration and invasion abilities, which are crucial to MM pathogenesis. Moreover, the gain of integrin-α8 expression mediated drug resistance against melphalan and bortezomib, which are the main therapeutic agents in MM. The cBioPortal genomic database revealed that ITGA8 have significant tendency to co-occur with PDGFRA and PDGFRB and their mRNA expression were up-regulated in ITGA8 overexpressed MM cells. In summary, integrin-α8, which was up-regulated in MM of early relapse, mediates EMT-like phenotype, enhancing migration and invasion; therefore, it could serve as a potential marker of MM relapse and be a new therapeutic target.

Factors contributing to the development of perceived stigma in people with newly diagnosed epilepsy: A one-year longitudinal study.

PURPOSE: We evaluated the course of perceived stigma and the factors associated with perceived stigma over the first year in newly diagnosed people with epilepsy (PWE). METHODS: We recruited newly diagnosed PWE from 12 tertiary hospitals in Korea. The perceived stigma of epilepsy was assessed using the Stigma Scale at baseline and one year later. At the time of diagnosis, demographic, clinical seizure-related, and psychological data were collected. The predictive factors for perceived stigma over one year were analyzed using logistic regression analyses. RESULTS: Two hundred eighteen newly diagnosed PWE were included at baseline, and 153 completed the study. The percentage of participants who felt stigmatized decreased from 30.7% at the time of diagnosis to 17.6% at the end of follow-up. Introverted personality and a high level of anxiety were independent factors contributing to stigma at the time of epilepsy diagnosis. At the one-year follow-up, introverted personality and lower economic status were predictive of the development of perceived stigma. CONCLUSION: Introverted personality was an important factor contributing to the development of perceived stigma at the time of diagnosis and at one year after diagnosis. In addition, a high level of anxiety and a low economic status were independently related to feelings of stigma at baseline and at one year after diagnosis, respectively. There may be a decrease in the perception of stigma over one year in newly diagnosed PWE.

Cross-regulation between protein L-isoaspartyl O-methyltransferase and ERK in epithelial mesenchymal transition of MDA-MB-231 cells.

AIM: Protein L-isoaspartyl O-methyltransferase (PIMT) regulates cell adhesion in various cancer cell lines through activation of integrin αv and the PI3K pathway. The epithelial mesenchymal transition (EMT) enables epithelial cells to acquire the characteristics of mesenchymal cells, and to allow them to migrate for metastasis. Here, we examined the relationship between PIMT and EMT with attached or detached MDA-MB 231 cells. METHODS: Human breast cancer cell line MDA-MB-231 cells were maintained in a suspension on poly-HEMA in the presence or absence of PIMT siRNA or ERK inhibitor PD98059. The mRNAs and proteins were analyzed using RT-PCR and immunoblotting, respectively. RESULTS: During cellular incubation under detached conditions, PIMT, integrin αv and EMT proteins, such as Snail, Slug and matrix metalloproteinase 2 (MMP-2), were significantly increased in correlation with the phosphorylation of ERK1/2. The ERK inhibitor PD98059 (25 µmol/L) strongly suppressed the expression of the proteins and PIMT. Interestingly, PIMT siRNA blocked the phosphorylation of ERK and the expression of the EMT proteins. Additionally, PIMT and ERK phosphorylation were both co-activated by treatment with TGF-ß (10 ng/mL) and TNF-α (10 ng/mL). CONCLUSION: A tight cross-regulation exists between ERK and PIMT in regards to their activation and expression during the EMT.

Protein L-isoaspartyl O-methyltransferase inhibits amyloid beta fibrillogenesis in vitro.

Fibrillar aggregates of beta-amyloid peptide (Abeta) are major constituents of the senile plaques found in the brains of patients suffering from Alzheimer's disease (AD). Previous studies have shown that spontaneous isomerization or racemization of aspartyl residues in Abeta peptides leads to conformational changes in the secondary structure and increased aggregative ability of the peptides. Protein L-isoaspartyl O-methyltransferase (PIMT, EC 2.1.1.77) is a repairing enzyme converting L-isoaspartyl/D-aspartyl residues in damaged proteins to normal L-aspartyl residues. In this study it was investigated, whether PIMT is able to modulate Abeta fibrillogenesis in vitro by methylation of isoaspartyl residue using purified 5Abeta and PIMT. A Thioflavin-T (Th-T) binding assay conducted after aging Abeta in vitro (37 degrees C, pH 7.4 in PBS) revealed that PIMT inhibited the increase of fluorescence caused by amyloid fibrillogenesis. Western blot analysis revealed that high molecular Abeta aggregates (> 200 kDa) only occurred during Abeta incubation, while they were reduced in response to incubation with PIMT and AdoMet. Additionally, circular dichroism (CD) showed that the beta-sheet structure was increased in Abeta peptides in a time-dependent fashion, while PIMT suppressed the beta-sheet transition after 24 h. Finally, transmission electron microscopy (TEM) revealed that PIMT reduced the size of the Abeta aggregates and induced a different pathway, leading to the formation of amorphous structures. Taken together, these findings indicate that isoaspartyl methylation leads to partial blockade of fibrillogenesis of Abeta by inhibiting the beta transition in the Abeta peptide.