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Objectives : To verify pain relief effects and allergy inhibitory action for the osteoarthritis of the knee joint in Sweet Bee Venom in which allergy causing enzyme is removed. Methods : We randomly allocated 30 participants to treatment group Sweet Bee Venom and Bee Venom. Outcomes on pain reduction were measured by 100mm VAS(Visual Analog Scale). And we recorded into details allergic responses during Pharmacopuncture treatment. Results : Whole body condition and pain rate through VAS measurement were improved significantly in 2 weeks. We could get difference in pain score of two Pharmacopuncture groups significantly in 2 weeks. Sweet BV group(0.1ß㎎/㎖) showed superior reduction in pain compared to the BV group(0.1ß㎎/㎖) significantly. And other allergic responses such as edema, itchiness, pain were significantly lower in the Sweet BV group.

Objectives : To verify pain relief effects and allergy inhibitory action for the osteoarthritis of the knee joint in Sweet Bee Venom in which allergy causing enzyme is removed. Methods : We randomly allocated 36 participants to treatment group Sweet Bee Venom and Bee Venom. Outcomes on pain reduction were measured by 100mm VAS(Visual Analog Scale). And we recorded into details allergic responses during Pharmacopuncture treatment. Results : Whole body condition and pain rate through VAS measurement were improved significantly in 2 weeks. We could get difference in pain score of two Pharmacopuncture groups significantly in 2 weeks. BV group showed superior reduction in pain compared to the Sweet BV group. But we could not get difference in whole score of two pharmacopuncture groups significantly. On the other hand other allergic responses such as edema, itchiness, pain were significantly lower in the Sweet BV group.

This phase II study assessed the efficacy and toxicity profile of a modified weekly irinotecan and cisplatin for chemotherapy-naïve patients with metastatic/recurrent esophageal squamous cell carcinoma (SQCC).The eligibility criteria included histologically confirmed esophageal SQCC, no prior chemotherapy, adequate organ functions and written informed consent. Patients received irinotecan 65 mg/m(2) plus cisplatin 30 mg/m(2) on days 1 and 8, every 3 weeks.Thirty-two patients were assessed for response and toxicity. Ten patients achieved a partial response (31.3%; 95% CI, 16.0-50.0%). With a median follow-up of 19.0 months, median progression-free and overall survival was 4.4 and 9.6 months, respectively, with a 1-year survival rate of 27.4%. Grade (G) 3/4 neutropenia was observed in 50.0% of the patients, which was the most common cause of dose reduction or therapy delay. G3 non-hematologic toxicity included seven (21.9%) asthenias, four (12.5%) diarrheas, and one (3.1%) nausea/vomiting, but no G4 non-hematologic toxicity was observed.This modified weekly irinotecan and cisplatin failed to ameliorate hematologic toxicity and to improve efficacy. However, easy administration and favorable non-hematologic toxicity as well as modest anti-tumor activity against metastatic or recurrent esophageal SQCC can make this regimen a potential treatment option, given the complexity of administration and toxicity of conventional infusional 5-FU and cisplatin.

To evaluate the safety and efficacy of CT-P13 (Remsima(®)) in patients with inflammatory bowel disease (IBD) in South Korea.This post-marketing study included patients with active moderate-to-severe Crohn's disease (CD), fistulizing CD (FCD), or moderate-to-severe ulcerative colitis (UC) treated with CT-P13 and followed for 30 weeks. Assessments included treatment-emergent adverse events (TEAEs) and disease-specific clinical response and remission.No unexpected TEAEs were observed in the 173 patients recruited to date. TEAEs occurred in 18.1, 16.7, and 26.9% of CD, FCD, and UC patients, respectively. Treatment-related TEAEs occurred in 10% of patients and were mostly mild-moderate in severity. There were five serious TEAEs (two infusion-related reactions, two infections, one abdominal pain) and no cases of malignancy, pneumonia, or death. Positive outcomes for response/remission were reported regardless of whether patients had received prior infliximab or not.CT-P13 was well tolerated and efficacious in patients with IBD.

This paper addresses how can we build an effective and profitable E- learning application for language learners. Most of applications in this kind has been developed authors; viewpoint. They frequently neglect what users really want. To be an application effective, users are interesting to access it. This naturally induces that applications should provide what users want according to their preferences. But existing applications are not capable of satisfying each user's preferences. For an alternative, this paper suggests on-line type applications that can provide unlimited number of contents on demand of users. It is believed that this makes applications sustainable at marketing viewpoint. In previous model, consumption is taken place just one time at the point of purchasing an application. But in this new model, consumption is taken place continuously whenever users consume contents provided by the applications.

Background: A combination of docetaxel (T) and capecitabine (X) showed synergistic effects in preclinical studies and phase III randomized trials of metastatic breast cancer. We conducted this phase II study to examine its efficacy in previously treated non-small cell lung cancer (NSCLC) patients. Methods: Patient eligibility required advanced NSCLC with measurable lesion(s), at least one prior regimen failure and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Treatment consisted of T 36 mg/m 2 i.v. on days 1 and 8 plus X 1000 mg/m 2 p.o. b.i.d. on days 1‐14 of a 21-day cycle (level I) or T 30 mg/m 2 i.v. on days 1 and 8 plus X 625 mg/m 2 p.o. b.i.d. on days 1‐14 of a 21-day cycle (level II). Results: A total of 35 patients (M/F ¼ 24/11) were enrolled; 29 had received one prior regimen and 19 had received platinum-based regimens. Significant non-hematologic toxicities were observed after the treatment given at level I, including one treatment-related death. Subsequently 29 patients were treated at level II. The treatment at level II was well tolerated with grade 3 or 4 neutropenia only in 10%, grade 3 asthenia in 21% and stomatitis in 14% of patients. Four (15%) of 27 evaluable patients had partial response (PR) at level II and eight (30%) had stable disease (SD). Conclusions: The TX regimen showed modest antitumor effects in patients with previously treated NSCLC. For further studies, we recommend T 30 mg/m 2 i.v. on days 1 and 8 plus X 625 mg/m 2 p.o. b.i.d. on days 1‐14 of a 21-day cycle.

BACKGROUND Combined chemotherapy with irinotecan and cisplatin (IP) is active in patients with nonsmall cell lung carcinoma (NSCLC). However, the optimal administration schedule needs to be defined to maximize its synergic effect. The authors evaluated the efficacy, toxicity, and pharmacokinetics (PK) of IP chemotherapy given on two administration sequences in chemotherapy-naive patients with NSCLC. METHODS Eighty eligible patients were assigned randomly to receive 1 of 2 irinotecan and cisplatin administration sequences on Day 1: irinotecan followed by cisplatin (I-P) (n = 39 patients) or cisplatin followed by irinotecan (P-I) (n = 41 patients). Treatment was comprised of irinotecan at a dose of 80 mg/m2 intravenously on Days 1 and 8 and cisplatin at a dose of 60 mg/m2 intravenously on Day 1 of a 21-day cycle for a maximum of 6 cycles. For PK analysis, serial plasma samples were obtained on Day 1 of the first cycle. RESULTS In total, 77 patients were assessable for efficacy. The overall response rate was 47%, and there was a trend in favor of P-I (54%) compared with I-P (39%). In multivariate logistic regression analysis, the P-I sequence and female gender were found to be significant predictors of a better response (P = 0.047 and P = 0.011, respectively). Overall toxicity profiles and PK parameters were similar in both arms. CONCLUSIONS IP chemotherapy showed promising activity with a favorable 1-year survival rate. For future clinical use, the authors recommend administering cisplatin first and then irinotecan, because that sequence was associated with a higher response rate. Cancer 2006. © 2006 American Cancer Society.

Recessed channel (Rch) structure n-MOSFET has been stressed under hot carrier injected condition and constant voltage stress (CVS). The degraded data are compared with planar channel (Pch) structure. We discuss difference of hot carrier (HC) degradation and oxide lifetime, which can be explained by the electrical field suppression and gate oxide thickness (tox) reduction in recessed channel area.

Dielectric reliability in Al2O3(2–3.1nm)–HfO2(3nm) stack capacitor with Metal–Insulator–Si(MIS) structure is investigated in this paper. We propose an optimized capacitor process through the Time–Dependent Dielectric Breakdown (TDDB) data under various process conditions. Furthermore, due to asymmetric current at both negative and positive voltage stress polarities, we show different lifetime extrapolation by a fluence–driven model. As a result, the maximum allowed operating voltage is projected to be 1.7V (failure rate 10ppm during 10year @ 85°C) for Data “0” retention lifetime.

Objective : This study is performed for the purpose of examining into the efficacy of the Bee Venom Acupuncture Treatment for Osteoarthritis of Knee Joint. Methods : We investigated 25 cases of patients with Osteoarthritis of Knee Joint from 1st June 2005 to 13th July 2005. The 25 patients were taken Bee Venom Acupuncture over three times irregularly. Treatment efficiency was monitored through VAS (Visual Analog Scale) and improvement degree of the grade of clinical symptoms. Conclusions : We brought to the conclusion that the Bee Venom Acupuncture has possibility to be efficient to cure the Osteoarthritis of Knee Joint patients. So we suggest the possibility to use this new remedy for the Osteoarthritis of Knee Joint.

Purpose Irinotecan plus cisplatin (IP) chemotherapy demonstrated a promising outcome with a high complete response (CR) rate in chemotherapy-naïve patients with extensive small-cell lung cancer (SCLC). We evaluated the efficacy of induction IP chemotherapy followed by concurrent etoposide plus cisplatin (EP) chemotherapy with twice-daily thoracic radiotherapy (TDTRT) in limited-disease SCLC (LD-SCLC). Patients and Methods Between November 2001 and May 2003, 35 chemotherapy-naïve patients with LD-SCLC were enrolled. Thirty-three patients (94%) were male, and 29 (83%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median age was 63 years. Treatment consisted of two 21-day cycles of cisplatin 40 mg/m2 and irinotecan 80 mg/m2 intravenously (IV) on days 1 and 8 followed by two 21-day cycles of cisplatin 60 mg/m2 IV on days 43 and 64, and etoposide 100 mg/m2 IV on days 43 to 45 and 64 to 66, with concurrent TDTRT of total 45 Gy beginning on day 43. Results All 35 patients were assessable for response. The objective response rate was 97% (CR, 3; partial response [PR], 31) after induction chemotherapy and 100% (CR, 15; PR, 20) after concurrent chemoradiotherapy (CCRT). After a median follow-up of 26.5 months, the median survival was 25.0 months (95% CI, 19.0 to 30.9) with 1- and 2-year overall survival rates of 85.7% and 53.9%, respectively. Median progression-free survival (PFS) was 12.9 months with a 1- and 2-year PFS of 58.5% and 36.1%, respectively. The most common toxicities were grade 3 or 4 neutropenia in 68% of patients during induction chemotherapy and 100% during CCRT. Febrile neutropenia occurred in 20% of patients during induction chemotherapy and 60% during CCRT. Conclusion IP induction chemotherapy followed by concurrent TDTRT with EP chemotherapy showed a promising activity with favorable 1- and 2-year survival rates. Based on the favorable outcome in this trial, this regimen should be evaluated in a large phase III trial.

Irinotecan/cisplatin (IP) is an active regimen for extensive-disease small-cell lung cancer (ED-SCLC). However, the optimal dose/schedule is unsettled. To evaluate the efficacy and safety of a dose-intensified, weekly concomitant administration of IP, we conducted a phase II study in chemo-naive patients with ED-SCLC. Between October 2001 and February 2004, 37 patients were enrolled. Twenty-nine (78%) were male, 21 (57%) had ECOG PS 0 or 1, and the median age was 62 yr. The initial six patients received cisplatin 50 mg/m2 followed by irinotecan 90 mg/m2 iv on d 1 and 8 of a 21-d cycle (dose level I), with one treatment-related death, three febrile neutropenias. Thereafter, the doses of cisplatin and irinotecan were reduced to 40 mg/m2 and 80 mg/m2, respectively (dose level II). The treatment was continued for up to six cycles. The overall response rate was 97%, with a complete response (CR) rate of 26%. The median duration of response was 6.4 mo (range, 1.6-13.1 mo). At a median follow-up of 27.3 mo, the median survival time was 11.1 mo and 1- and 2-yr survival rates were 44.1% and 11.8%, respectively. The median progression-free survival (PFS) was 6.0 mo (range, 1.5-13.1 mo) and 1-year PFS rate was 7%. Major grade 3 or 4 toxicities included neutropenia (89%), anemia (59%), and diarrhea (27%). Despite of significant myelosuppresion, this dose-intensified weekly concomitant administration of cisplatin and irinotecan was feasible. This dose-schedule showed promising activity with high rate of complete remission in patients with ED-SCLC.

The heterodimeric c-Jun/c-Fos, an activator protein-1 (AP-1) has been implicated in mesoderm induction (Dong et al., 1996; Kim et al., 1998) whereas the homodimer of c-Jun was reported to be involved in neural inhibition during the early development of Xenopus embryos. During the early vertebrate development AP-1 involvement in the neural induction is still not clearly understood. We report here that AP-1 has a role in Zic3 expression, a critical proneural gene and a primary regulator of neural and neural crest development (Nakata et al., 1997; Nakata et al., 1998). AP-1 was able to induce the Zic3 gene in a dose dependent manner but other homo- or hetero-dimeric proteins, such as c-Jun/c-Jun, JunD/FosB or JunD/Fra-1 were not. The inhibition of AP-1 activity using morpholino antisenses of c-jun mRNAs blocked the Zic3 expression induced by activin. In addition, co-injection of c-jun mRNA rescued the down-regulated Zic3 expression. The promoter region of isolated Zic3 genomic DNA was found to possess several consensus-binding site of AP-1. Thus, in the functional assays, AP-1 could increase promoter activity of Zic3 gene. These findings suggest that proneural gene, Zic3 may be regulated by heterodimeric AP-1(c-Jun/c-Fos) and it may have a role in activin signaling for the regulation of neural specific gene, Zic3.

Fibroblast growth factor (FGF) is established as an initiator of signaling events critical for neurogenesis and mesoderm formation during early Xenopus embryogenesis. However, less is known about the role FGF signaling plays in endoderm specification. Here, we show for the first time that endoderm-specific genes are induced when FGF signaling is blocked in animal cap explants. This block of FGF signaling is also responsible for a significant enhancement of endodermal gene expression in animal cap explants that are injected with a dominant-negative BMP-4 receptor (DNBR) RNA or treated with activin, however, neural and mesoderm gene expression is diminished. Consistent with these results, the injection of dominant-negative FGF receptor (DNFR) RNA expands endodermal cell fate boundaries while FGF treatment dramatically reduces endoderm in whole embryos. Taken together, these results indicate that inhibition of FGF signaling promotes endoderm formation, whereas the presence of active FGF signaling is necessary for neurogenesis/mesoderm formation.

We have demonstrated a novel three-dimensional multibridge-channel metal-oxide-semiconductor field-effect transistor (MBCFET). This transistor was successfully fabricated using a conventional complementary metal-oxide-semiconductor process. We introduce the fabrication technologies and electrical characteristics of MBCFET in comparison with a conventional planar MOSFET. The MBCFET has more benefits than a conventional MOSFET. It shows 4.6 times larger current drivability than a planar MOSFET. This is due to the vertically stacked multibridge channels. The subthreshold swing of MBCFET is 61 mV/dec, which is almost an ideal value due to the thin body surrounded by gate. Based on a simulation result, we show that the MBCFET will have a large on-off state current ratio at short channel transistors.

PV.1, a homeotic protein, ventralizes dorsal mesoderm and inhibits neuralization by mediating BMP-4 signaling in Xenopus embryo. In our previous report antimorphic PV.1 causes a secondary axis by inducing the ectopic organizer. We analyzed the structure of this transcription factor through domain level assessment. In a phenotype-inducing test, half of the N-terminus at the N-terminal side was unessential for inducing ventralization of embryos. We examined the transacting activity of several regions of PV.1 utilizing GAL4 hybrid system. The C-terminal region/GAL4DBD (DNA binding domain) exhibited strong repressive activity on a reporter gene (operator/promoter/reporter; Gal4-TK-luc) as much as the whole polypeptide/GAL4DBD, whereas the N-terminal region/GAL4DBD showed only modest repression. The results suggest that PV.1 functions as a transcriptional repressor and this repressive activity is localized mostly to the C-terminal region. Additional characterizations of N- and C-terminus with respect to the effects on the expression of other genes are described.

Combination chemotherapy for the treatment of pancreatic cancer commonly employs gemcitabine with an EGFR inhibitor such as erlotinib. Here, we show that the retinoic acid derivative, ABPN, exhibits more potent anticancer effects than erlotinib, while exhibiting less toxicity toward noncancerous human control cells. Low micromolar concentrations of ABPN induced apoptosis in BxPC3 and HPAC pancreatic cancer cell lines, concomitant with a reduction in phosphorylated EGFR as well as decreased ErbB3, Met and BRUCE protein levels. The degradation of ErbB3 is a result of proteasomal degradation, possibly due to the ABPN-dependent upregulation of Nrdp1. Administration of ABPN showed significant reductions in tumor size when tested using a mouse xenograft model, with higher potency than erlotinib at the same concentration. Analysis of the tumors demonstrated that ABPN treatment suppressed ErbB3 and Met and induced Nrdp1 in vivo. The data suggest that ABPN may be more suitable in combination chemotherapy with gemcitabine than the more widely used EGFR inhibitor, erlotinib.

Xvent homeobox proteins are induced by BMP-4 signaling and have been known to mediate many BMP-4 activities as key downstream transcriptional factors. In order to investigate the regulatory mode of Xvent transcription, we isolated genomic DNA of the Xbr-1a/Xvent-2 containing the promoter region responsive to BMP-4 signaling. The cis-acting elements located within the Xbr-1a/Xvent-2 promoter and the regulation modes by BMP-4 signaling were analyzed by serial deletion and site-directed mutagenesis experiments. The upstream )235 bp of the promoter retained the full transcriptional activity and BMP-4-response when compared with the longest promoter construct. Further analysis indicated that two separated 15 bp regions contained a strong positive element and BMP-4-response element. Site-directed mutagenesis of those regions suggests that those two regions cooperate for the promoter activity and BMP-4-response. Moreover, we found that the transcription factors, Oaz and PEBP2aA, were able to elicit additive effects with BMP-4 signaling on Xbr-1a/Xvent-2 reporter activities. These results indicate that transcriptional regulation of the Xbr-1a/Xvent-2 gene occurs in a complex mode through the cooperation of various transcription factors. 2002 Elsevier Science (USA). All rights reserved.

510 Background: CT-P6 (C) is a proposed biosimilar to trastuzumab. This trial (NCT02162667) evaluated the similarity of C and trastuzumab in efficacy and safety for HER2+ EBC. Methods: 549 patients with HER2+ EBC were randomized to receive C (n=271) or trastuzumab (n=278) in combination with docetaxel (Cycles 1-4) and 5-fluorouracil, epirubicin, and cyclophosphamide (Cycles 5-8). C or trastuzumab was administered at 8 mg/kg (Cycle 1 only) followed by 6 mg/kg every 3 weeks. The primary endpoint was pathological complete response (pCR) rate at surgery. Secondary endpoints were overall response rate (ORR), PK, PD and safety. After surgery, patients received adjuvant C or trastuzumab to complete a total of 1-year treatment. Results: The pCR rate was 46.8% for C and 50.4% for trastuzumab. The 95% CIs for the risk ratio estimate were within the equivalence margin (0.74, 1.35) in PPS and ITT analyses. Other efficacy endpoints were similar between C and trastuzumab. The proportion of patients with at least 1 treatment-emergent SAE was 6.6% for C and 7.6% for trastuzumab. Only 1 patient in each group withdrew treatment due to significant LVEF decrease. Infusion-related reaction was reported for 8.5% of patients in C and 9.0% of patients in trastuzumab. Conclusions: This study demonstrated the similarity of efficacy in terms of pCR between CT-P6 and trastuzumab in EBC patients. Secondary efficacy endpoints also supported the similarity between CT-P6 and trastuzumab. CT-P6 was well tolerated with a similar safety profile to that of trastuzumab during the neoadjuvant period. Clinical trial information: NCT02162667. [Table: see text]

Non-small-cell lung cancer (NSCLC) is associated with diverse genetic alterations including mutation of epidermal growth factor receptor (EGFR). Isoliquiritigenin (ILQ), a chalcone derivative, possesses anticancer activities. In the present study, we investigated the effects of ILQ on the growth of tyrosine kinase inhibitor (TKI)-sensitive and -resistant NSCLC cells and elucidated its underlying mechanisms. Treatment with ILQ inhibited growth and induced apoptosis in both TKI-sensitive and -resistant NSCLC cells. ILQ-induced apoptosis was associated with the cleavage of caspase-3 and poly-(ADP-ribose)-polymerase, increased expression of Bim, and reduced expression of Bcl-2. In vitro kinase assay results revealed that ILQ inhibited the catalytic activity of both wild type and double mutant (L858R/T790M) EGFR. Treatment with ILQ inhibited the anchorage-independent growth of NIH3T3 cells stably transfected with either wild type or double-mutant EGFR with or without EGF stimulation. ILQ also reduced the phosphorylation of Akt and ERK1/2 in both TKI-sensitive and -resistant NSCLC cells, and attenuated the kinase activity of Akt1 and ERK2 in vitro. ILQ directly interacted with both wild type and double-mutant EGFR in an ATP-competitive manner. A docking model study showed that ILQ formed two hydrogen bonds (Glu-762 and Met-793) with wild type EGFR and three hydrogen bonds (Lys-745, Met-793, and Asp-855) with mutant EGFR. ILQ attenuated the xenograft tumor growth of H1975 cells, which was associated with decreased expression of Ki-67 and diminished phosphorylation of Akt and ERK1/2. Taken together, ILQ suppresses NSCLC cell growth by directly targeting wild type or mutant EGFR.

This study was intended to evaluate the environmental impact, and potential improvements for a typical tractor model (LT360D) of LG Machinery Co., Ltd. The life cycle of this study includes all stages from raw material acquisition up to final disposal. The eco-indicator 95 method was employed to perform an impact assessment. The result of this study is expected to represent the environmental feature of typical diesel vehicles at each life cycle stage. This study is a starting point of building life cycle inventories for typical off-road diesel tractors. With this result, environmental weak points of the tractor have been defined, and major improvement strategies have been set up to develop the ‘Green Tractor’.

We tried to prevent the mitochondrial and DNA damage caused by mechanical stress-associated reactive oxygen species (ROS), and to improve the reprogramming of bovine somatic cell nuclear transfer (SCNT) embryos by antioxidant treatment during the manipulation procedures of SCNT. Bovine recipient oocytes and reconstituted oocytes were treated with antioxidants during manipulation procedures. The H2O2 level, mitochondrial morphology, membrane potential and apoptosis at the one-cell stage, and in vitro development and DNA methylation status of blastocysts were evaluated. Antioxidant treatment during manipulation procedures reduced the H2O2 level of SCNT embryos. Antioxidant-treated SCNT embryos normally formed mitochondrial clumps, similar to IVF embryos, and showed higher mitochondrial membrane potential versus the SCNT control (P

During Xenopus early development, FGF signaling is involved in mesoderm formation and neurogenesis by modulating various signaling cascades. FGF-MAPK signaling induces Xbra expression, which maintains mesodermal fate through an autocatalytic-loop. Interestingly, previous reports have demonstrated that basic FGF (bFGF) treatment alone does not induce neurogenesis in ectodermal explants, even though FGF signaling inhibits BMP signaling via phosphorylation in Smad1 linker region. In addition, the overexpression of dominantnegative Xbra induces neurogenesis in ectodermal explants. However, the detailed mechanism underlying these phenomena has not yet been clarified. In this work, we showed that bFGF-Xbra signaling increased the PV.1 expression. DN-Xbra was found to decrease PV.1 expression, and the co-injection of PV.1 with DN-Xbra reduced neurogenesis in ectodermal explants. Furthermore, the knockdown of PV.1 induced neurogenesis in bFGF-treated ectodermal explants. Taken together, our results demonstrate that FGF-Xbra signaling induces PV.1 expression and that PV.1 functions as a neural repressor in the FGF-treated ectoderm. [BMB Reports 2014; 47(12): 673-678]

Lung cancer is a leading cause of death worldwide and MET amplification is a major therapeutic limitation in acquired-resistance lung cancer. We hypothesized that butein, a phytochemical, can overcome gefitinib-induced resistance by targeting both EGFR and MET in non-small cell lung cancer (NSCLC). To investigate the ability of butein to target EGFR and MET, we used in silico docking, a library of natural compounds and kinase assays. The effects of butein on growth, induction of apoptosis and expression of EGFR/MET signaling targets were examined in HCC827 (gefitinib-sensitive) and HCC827GR (gefitinib-resistant) NSCLC cells. Results were confirmed in vivo by a HCC827 or HCC827GR cell xenograft mouse model, each treated with vehicle, butein or gefitinib. Butein inhibited phosphorylation and kinase activity of EGFR and MET as well as soft agar colony formation and decreased viability of HCC827 and HCC827GR cells. Butein increased apoptosis-related protein expression in these cells. Results were confirmed by co-treatment with inhibitors of EGFR/MET or double knock-down. Finally, xenograft study results showed that butein strongly suppressed HCC827 and HCC827GR tumor growth. Immunohistochemical data suggest that butein inhibited Ki-67 expression. These results indicate that butein has potent anticancer activity and targets both EGFR and MET in acquired-resistance NSCLC.

Of 18 vanA-positive vancomycin-susceptible Enterococcus faecium isolates, vanRS in the vanA cluster was detected in all isolates, while vanHAX was detected in only 2 isolates. Following exposure to glycopeptides, 22.2% of vancomycin-susceptible E. faecium (VSE) converted into vancomycin-resistant E. faecium. The vanA cluster of the revertant mutant was transferred to the VSE isolates.

Purpose: Common treatment modalities for non–small cell lung cancer (NSCLC) involve the EGF receptor-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib. However, the vast majority of treated patients acquire resistance to EGFR-TKIs, due, in large part, to secondary mutations in EGFR or amplification of the MET gene. Our purpose was to test ubiquitin-specific peptidase 8 (USP8) as a potential therapeutic target for gefitinib-resistant and -sensitive non–small cell lung cancer (NSCLC). Experimental Design: Testing the effect of knockdown of USP8 and use of a synthetic USP8 inhibitor to selectively kill gefitinib-resistant (or -sensitive) NSCLCs with little effect on normal cells in cell culture and a xenograft mouse model. Results: Knockdown of ubiquitin-specific peptidase 8 (USP8) selectively kills gefitinib-resistant NSCLCs while having little toxicity toward normal cells. Genetic silencing of USP8 led to the downregulation of several receptor tyrosine kinases (RTK) including EGFR, ERBB2, ERBB3, and MET. We also determined that a synthetic USP8 inhibitor markedly decreased the viability of gefitinib-resistant and -sensitive NSCLC cells by decreasing RTK expression while having no effect on normal cells. Moreover, treatment with a USP8 inhibitor led to significant reductions in tumor size in a mouse xenograft model using gefitinib-resistant and -sensitive NSCLC cells. Conclusions: Our results show for the first time that the inhibition of USP8 activity or reduction in USP8 expression can selectively kill NSCLC cells. We propose USP8 as a potential therapeutic target for gefitinib-resistant and -sensitive NSCLC cells. Clin Cancer Res; 19(14); 3894–904. ©2013 AACR.

The tumor suppressor protein p16(INK4a) is a member of the INK4 family of cyclin-dependent kinase (Cdk) inhibitors, which are involved in the regulation of the eukaryotic cell cycle. However, the mechanisms underlying the anti-proliferative effects of p16(INK4a) have not been fully elucidated. Using yeast two-hybrid screening, we identified the eukaryotic elongation factor (eEF)1A2 as a novel interacting partner of p16(INK4a). eEF1A2 is thought to function as an oncogene in cancers. The p16(INK4a) protein interacted with all but the D2 (250-327 aa) domain of eEF1A2. Ectopic expression of p16(INK4a) decreased the expression of eEF1A2 and inhibited cancer cell growth. Furthermore, suppression of protein synthesis by expression of p16(INK4a) ex vivo was verified by luciferase reporter activity. Microinjection of p16(INK4a) mRNA into the cytoplasm of Xenopus embryos suppressed the luciferase mRNA translation, whereas the combination of p16(INK4a) and morpholino-eEF1A2 resulted in a further reduction in translational activity. We conclude that the interaction of p16(INK4a) with eEF1A2, and subsequent downregulation of the expression and function of eEF1A2 is a novel mechanism explaining the anti-proliferative effects of p16(INK4a).

Abnormal functioning of multiple gene products underlies the neoplastic transformation of cells. Thus, chemopreventive and/or chemotherapeutic agents with multigene targets hold promise in the development of effective anticancer drugs. Silybin, a component of milk thistle, is a natural anticancer agent. In the present study, we investigated the effect of silybin on melanoma cell growth and elucidated its molecular targets. Our study revealed that silybin attenuated the growth of melanoma xenograft tumors in nude mice. Silybin inhibited the kinase activity of mitogen-activated protein kinase (MEK)-1/2 and ribosomal S6 kinase (RSK)-2 in melanoma cells. The direct binding of silybin with MEK1/2 and RSK2 was explored using a computational docking model. Treatment of melanoma cells with silybin attenuated the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and RSK2, which are regulated by the upstream kinases MEK1/2. The blockade of MEK1/2-ERK1/2-RSK2 signaling by silybin resulted in a reduced activation of NF-κB, activator protein-1, and STAT3, which are transcriptional regulators of a variety of proliferative genes in melanomas. Silybin, by blocking the activation of these transcription factors, induced cell-cycle arrest at the G1 phase and inhibited melanoma cell growth in vitro and in vivo. Taken together, silybin suppresses melanoma growth by directly targeting MEK- and RSK-mediated signaling pathways. Cancer Prev Res; 6(5); 455–65. ©2013 AACR.

Highly manufacturable partially insulated field-effect transistors (PiFETs) were fabricated by using Si-SiGe epitaxial growth and selective SiGe etch process. Owing to these technologies, pseudo-silicon-on-insulator (SOI) structures, partially insulating oxide (PiOX) under source/drain (PUSD) and PiOX under channel (PUC), could be easily realized with excellent structural and process advantages. We are demonstrating their preliminary characteristics and properties. Especially, in the PUSD PiFET, junction capacitance, leakage current, and DIBL in bulk devices could be reduced and the floating body problem in SOI devices was also cleared without any area penalty. Thus, this PiFET structure can be a promising candidate for the future DRAM cell transistor.

We successfully fabricated the three-dimensional multibridge channel MOSFET (MBCFET) with the channel length of 240 nm by using epitaxial growth technology and damascene gate process. Its subthreshold swing is 60 mV/dec, a nearly ideal value, resulting from the thin body completely surrounded by the gate. And its current drivability is 4.6 times larger than that of a planar dynamic random access memory (DRAM) MOSFET. This outstanding performance of MBCFET originates from the vertically increased width due to the multibridge channel, and the enhanced mobility due to the reduced vertical electric field in the thin body.

Activator protein-1 (AP-1) regulates a wide range of cellular processes including proliferation, differentiation, and apoptosis. As a transcription factor, AP-1 is commonly found as a heterodimer comprised of c-Jun and c-Fos proteins. However, other heterodimers may also be formed. The function of these dimers, specifically the heterodimeric AP-1 comprised of JunD and c-Fos (AP-1(JunD/c-Fos)), has not been elucidated. Here, we identified a function of AP-1(JunD/c-Fos) in Xenopus hematopoiesis. A gain-of-function study performed by overexpressing junD and c-fos and a loss-of-function study using morpholino junD demonstrate a critical role for AP-1(JunD/c-Fos) in hematopoiesis during Xenopus embryogenesis. Additionally, we confirmed that JunD of AP-1(JunD/c-Fos) is required for BMP-4-induced hematopoiesis. We also demonstrated that BMP-4 regulated JunD activity at the transcriptional regulation and post-translational modification levels. Collectively, our findings identify AP-1(JunD/c-Fos) as a novel hematopoietic transcription factor and the requirement of AP-1(JunD/c-Fos) in BMP-4-induced hematopoiesis during Xenopus hematopoiesis.

Various types of post-translational modifications of the histone tails have been revealed, but a few modifications have been found within the histone core sequences. Histone core post-translational modifications have the potential to modulate nucleosome structure and DNA accessibility. Here, we studied the histone H2B core domain and found that phosphorylation of H2B serine 32 occurs in normal cycling and mitogen-stimulated cells. Notably, this phosphorylation is elevated in skin cancer cell lines and tissues compared with normal counterparts. The JB6 Cl41 mouse skin epidermal cell line is a well established model for tumor promoter-induced cell transformation and was used to study the function of H2B during EGF-induced carcinogenesis. Remarkably, cells overexpressing a nonphosphorylatable H2BS32A mutant exhibited suppressed growth and EGF-induced cell transformation, possibly because of decreased activation of activator protein-1, compared with control cells overexpressing wild type H2B. We identified ribosomal S6 kinase 2 (RSK2) as the kinase responsible for H2BS32 phosphorylation. Serum-starved JB6 cells contain very little endogenous H2BS32 phosphorylation, and EGF treatment induced this phosphorylation. The phosphorylation was attenuated in RSK2 knock-out MEFs and RSK2 knockdown JB6 cells. Taken together, our results demonstrate a novel role for H2B phosphorylation in cell transformation and show that H2BS32 phosphorylation is critical for controlling activator protein-1 activity, which is a major driver in cell transformation.

Background Activator protein-1 (AP-1) is a mediator of BMP or FGF signaling during Xenopus embryogenesis. However, specific role of AP-1 in activin signaling has not been elucidated during vertebrate development. Methodology/Principal Findings We provide new evidence showing that overexpression of heterodimeric AP-1 comprised of c-jun and c-fos (AP-1c-Jun/c-Fos) induces the expression of BMP-antagonizing organizer genes (noggin, chordin and goosecoid) that were normally expressed by high dose of activin. AP-1c-Jun/c-Fos enhanced the promoter activities of organizer genes but reduced that of PV.1, a BMP4-response gene. A loss of function study clearly demonstrated that AP-1c-Jun/c-Fos is required for the activin-induced organizer and neural gene expression. Moreover, physical interaction of AP-1c-Jun/c-Fos and Smad3 cooperatively enhanced the transcriptional activity of goosecoid via direct binding on this promoter. Interestingly, Smad3 mutants at c-Jun binding site failed in regulation of organizer genes, indicating that these physical interactions are specifically necessary for the expression of organizer genes. Conclusions/Significance AP-1c-Jun/c-Fos plays a specific role in organizer gene expression in downstream of activin signal during early Xenopus embryogenesis.

In early vertebrate development, mesoderm induction is a crucial event regulated by several factors including the activin, BMP and FGF signaling pathways. While the requirement of FGF in Nodal/activin-induced mesoderm formation has been reported, the fate of the tissue modulated by these signals is not fully understood. Here, we examined the fate of tissues when exogenous activin was added and FGF signaling was inhibited in animal cap explants of Xenopus embryos. Activin-induced dorsal mesoderm was converted to ventral mesoderm by inhibition of FGF signaling. We also found that inhibiting FGF signaling in the dorsal marginal zone, in vegetal-animal cap conjugates or in the presence of the activin signaling component Smad2, converted dorsal mesoderm to ventral mesoderm. The expression and promoter activities of a BMP responsive molecule, PV.1 and a Spemann organizer, noggin, were investigated while FGF signaling was inhibited. PV.1 expression increased, while noggin decreased. In addition, inhibiting BMP-4 signaling abolished ventral mesoderm formation induced by exogenous activin and FGF inhibition. Taken together, these results suggest that the formation of dorso-ventral mesoderm in early Xenopus embryos is regulated by a combination of FGF, activin and BMP signaling.

In this paper, the advanced process has been presented to remove the WSix peeling which was brought in sub-100 nm DRAM SRCAT(sphere-shaped-recess-channel-array transistor). The source of WSix peeling was proved to be the groove of gate poly film. We have completely solved the problems to adopt the gate-poly CMP (chemical mechanical polishing) process.

We have observed new charge trapping phenomena in sub-80-nm DRAM recessed- channel-array-transistor (RCAT) after Fowler-Nordheim (FN) stress. Gate stack process strongly affected the charge trapping and the trap generating in oxide bulk and interface of RCAT. According to the trapped charges and/or the generated traps after FN stress, the data retention time and writing capabilities of DRAM were dramatically changed. We have summarized the electrical characteristics of RCAT fabricated with different gate stack processes.

BACKGROUND. The current study was performed to compare the nonplatinum-based combination of gemcitabine and vinorelbine (GV) with the combination of irinotecan and cisplatin (IP) as first-line chemotherapy with second-line crossover in patients with advanced nonsmall cell lung cancer (NSCLC). METHODS. Patients were randomly assigned to received either irinotecan at a dose of 65 mg/m2 plus cisplatin at a dose of 30 mg/m2 (Arm A) or gemcitabine at a dose of 900 mg/m2 plus vinorelbine at a dose of 25 mg/m2 (Arm B), each of which was administered on Days 1 and 8 every 3 weeks as the first-line therapy followed by crossover at the time of disease progression. RESULTS. A total of 146 patients were enrolled (75 patients in Arm A and 71 patients in Arm B); 138 patients were evaluable for tumor response and toxicity. During first-line therapy, IP was found to result in more grade 2+ nausea and vomiting (toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) (41% vs 12%; P = .0001) and alopecia (36% vs 10%; P = .0003). Pneumonitis was noted only with GV therapy (7% vs 0%; P = .058). During second-line therapy, IP was found to result in more grade 3 diarrhea (17% vs 2%; P = .039) and GV featured more cases of grade 3+ neutropenia (78% vs 40%; P = .0003). IP tended to generate more tumor responses (38% vs 26% as first-line therapy, and 30% vs 13% as second-line therapy) compared with GV. IP also demonstrated a favorable trend in median progression-free survival (4.6 months vs 3.8 months as first-line therapy and 4.5 months vs 2.6 months as second-line therapy) and overall survival (15.9 months vs 13.1 months; P = .3), but this difference was not statistically significant. The majority of patients who were refractory to IP also failed to respond to GV in the second-line setting. CONCLUSIONS. The platinum-based IP regimen appeared to be superior to the GV combination in terms of response rate. However, given the similar survival and better tolerability of the nonplatinum GV regimen, either treatment sequence would appear to be acceptable for the treatment of patients with advanced NSCLC. Cancer 2008. © 2008 American Cancer Society.

In high voltage transistor (HVT), device characteristics could be affected by little changes of doping concentration or parasitic charges due to low substrate doping concentrations. Humps caused by boron segregation in sub-threshold region of HVT make bad effects on device characteristics. In this paper, we have presented the novel Fermi leve controlled HVT (FCHVT) to simply eliminate hump effects.

As design rule is scaled down in complementary metal-oxide-semiconductor (CMOS) device, the several disadvantages based on electric field effect in CMOS device were emerged such as short channel effect, junction leakage and gate oxide leakage current (J.D. Meindl, 2001). Non-CMOS based device using micro/nanoelectromechanical systems (MEMS/NEMS) switch have been proposed as one of the alternatives (R.L. Badzey et al., 2004), (Abele et al., 2006), (W.W. Jang et al., 2007). Devices based on MEMS/NEMS switch show excellent on-off current characteristics due to an almost zero off current and abrupt on-off current transition. Also, they have robustness under harsh environments such as X-ray, radiation, and low/high temperature. In this work, two types of two terminal NEMS switch with the smallest dimensions ever made were proposed and fabricated. Moreover, their electrical characteristics were provided.

Recently, having vertically stacked arrays of 3D channels, multi-bridge-channel MOSFETs (MBCFETs) have been fabricated successfully (Lee et al., 2003). In this paper, we report temperature dependent transport characteristics of the MBCFET.

To define an integrated pharmacogenetic model for predicting irinotecan pharmacokinetic (PK) and severe toxicity, we evaluated multivariate analysis using 15 polymorphisms within seven genes with putative influence on metabolism and transport of irinotecan. A total of 107 NSCLC patients treated with irinotecan were evaluated for PK and genotyped for the UGT1A1*6, UGT1A1*28, UGT1A9*22, ABCB11236C>T, 2677G>T/A, 3435C>T, ABCC2-24C>T, 1249G>A, 3972C>T, ABCG234G>A, 421C>A, and SLCO1B1 -11187G>A, 388A>G, and 521T>C, and CYP3A5*3 polymorphisms. Multivariate linear and logistic regression analyses including genotypes and clinicopathologic factors were performed. SN-38 AUC was significantly correlated with ANCs (r=-0.3, p=0.009) and grade 4 neutropenia (p=0.01). The UGT1A1*6/*6, UGT1A9*1/*1 or *1/*22, and SLCO1B1 521TC or CC genotypes, and female-gender were predictive for higher AUC(SN-38) in multivariate analysis. Among them, SLCO1B1 521TC or CC and UGT1A1*6/*6 genotypes were independently predictive for grade 4 neutropenia in multivariate analysis (OR=3.8 and 7.4, respectively). Although no significant association was observed between PK parameters and grade 3 diarrhea, UGT1A9*1/*1, ABCC23972CC, and ABCG234GA or AA genotypes were independently predictive for grade 3 diarrhea in multivariate analysis (OR=6.3, 5.6, and 5.1, respectively). Patient selection based on integrated pharmacogenetic model would be helpful for predicting irinotecan-PK and severe toxicities in NSCLC patients.

The X-ray structure at 2.0-A resolution of the p90 ribosomal S6 kinase 2 C-terminal kinase domain revealed a C-terminal autoinhibitory alphaL-helix that was embedded in the kinase scaffold and determines the inactive kinase conformation. We suggest a mechanism of activation through displacement of the alphaL-helix and rearrangement of the conserved residue Glu500, as well as the reorganization of the T-loop into the active conformation.

BACKGROUND. The authors investigated whether ABCB1, ABCC2, and ABCG2 genetic polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of patients with advanced nonsmall cell lung cancer (NSCLC). METHODS. Blood samples from 107 NSCLC patients treated with irinotecan and cisplatin chemotherapy were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCC2 (−24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. Genotypes were correlated with irinotecan-PK, toxicity, tumor response, and survival. RESULTS. Among 8 polymorphisms, 3435TT and 2677TT were associated with AUCSN-38G and CLSN-38G. When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUCSN-38G (P = .006), whereas 2677GG/3435CC carriers showed significantly higher AUCSN-38 (P = .039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1st cycle (P = .012) as well as entire course of chemotherapy (P = .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P = .047). In tumor response, ABCC2 −24TT and 3972TT genotypes were associated with higher response rates (P = .031 and .046, respectively) and longer progression-free survival (P = .035 and .038, respectively), which was sustained in haplotype analysis. CONCLUSIONS. Specific polymorphisms of ABCB1 and ABCC2 can influence disposition and tumor response to irinotecan by regulating transporter activity. These findings may help to individualize irinotecan-based chemotherapy in patients with advanced NSCLC. Cancer 2007. © 2007 American Cancer Society.

We compared electrical characteristics of TBCFET (Triple-Bridge-Channel MOSFET), MBCFET (Multi-Bridge-Channel MOSFET) and SBCFET (Single-Bridge-Channel MOSFET) with sub-20 nm gates. TBCFET is suitable for low-power application with 2.9 mA/um of on-state current and SNM (static noise margin) of 320 mV even at Vdd = 0.8V MBCFET and SBCFET, that are applicable to high-performance devices, show 4.17 mA/um and 2.16 mA/um of on-state currents at V^ = 1.0 V, respectively.