Search

In the past few decades, solid evidence has been accumulated for the pivotal significance of immunoinflammatory processes in the initiation, progression, and exacerbation of many diseases and disorders. This groundbreaking view came from original works by Ross who first described that excessive inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall is essential for the pathogenesis of atherosclerosis (Ross, Nature 1993; 362(6423): 801–9). It is now widely recognized that both innate and adaptive immune reactions are avidly involved in the inflammation-related remodeling of many tissues and organs. When this state persists, irreversible fibrogenic changes would occur often culminating in fatal insufficiencies of many vital parenchymal organs such as liver, lung, heart, kidney and intestines. Thus, inflammatory diseases are becoming the common life-threatening risk for and urgent concern about the public health in developed countries (Wynn et al., Nature Medicine 2012; 18(7): 1028–40). Considering this timeliness, we organized a special symposium entitled “Implications of immune/inflammatory responses in smooth muscle dysfunction and disease” in the 58th annual meeting of the Japan Society of Smooth Muscle Research. This symposium report will provide detailed synopses of topics presented in this symposium; (1) the role of inflammasome in atherosclerosis and abdominal aortic aneurysms by Fumitake Usui-Kawanishi and Masafumi Takahashi; (2) Mechanisms underlying the pathogenesis of hyper-contractility of bronchial smooth muscle in allergic asthma by Hiroyasu Sakai, Wataru Suto, Yuki Kai and Yoshihiko Chiba; (3) Vascular remodeling in pulmonary arterial hypertension by Keizo Hiraishi, Lin Hai Kurahara and Ryuji Inoue.

Dexamethasone for antiemetic therapy is typically administered with anticancer drugs such as cisplatin. We previously reported that cisplatin upregulates the muscle-specific E3 ubiquitin ligase genes, namely muscle ring-finger protein 1 (MuRF1) and atrophy gene-1 (atrogin-1), and promotes muscle atrophy in mice. It is well known that dexamethasone causes upregulation of MuRF1 and Atrogin-1 expression in skeletal muscles. Although it is speculated that a combination of dexamethasone and cisplatin worsens muscle atrophy, there are no reports based on research. We thereby investigated the effects of cisplatin and dexamethasone, alone or in combination, on the expression of MuRF1 and Atrogin-1 in murine skeletal muscles and C2C12 myotubes. Mice were intraperitoneally injected with cisplatin or the vehicle control once daily for 4 days. Dexamethasone or the vehicle control was subcutaneously administered 30 minutes prior to the administration of cisplatin. Dexamethasone enhanced MuRF1 and Atrogin-1 gene expression upregulated by cisplatin in murine quadriceps muscles and C2C12 myotubes. Cisplatin-caused upregulation of myostatin and downregulation of IGF-1 gene expression were also enhanced by co-administration of dexamethasone in murine quadriceps muscles and C2C12 myotubes. This study shows that the combination treatment of cisplatin and dexamethasone exacerbated muscle atrophy in mice. Therefore, this treatment regimen might exacerbate muscle atrophy in cancer patients.

Determinants of interindividual variability in erlotinib pharmacokinetics (PK) and adverse events remain to be elucidated. This study with 50 Japanese non-small-cell lung cancer patients treated with oral erlotinib at a standard dose of 150 mg aimed to investigate whether genetic polymorphisms affect erlotinib PK and adverse events. Single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, and GSTT1) or efflux transporters (ABCB1, and ABCG2) were analyzed as covariates in a population PK model. The ABCB1 1236C>T (rs1128503) polymorphism, not ABCB1*2 haplotype (1236TT-2677TT-3455TT, rs1128503 TT-rs2032582 TT-rs1045642 TT), was a significant covariate for the apparent clearance (CL/F), with the TT genotype showing a 29.4% decrease in CL/F as compared with the CC and the CT genotypes. A marginally higher incidence of adverse events (mainly skin rash) was observed in the TT genotype group; however, patients with high plasma erlotinib exposure did not always experience skin rash. None of the other SNPs affected PK or adverse events. The ABCB1 genotype is a potential predictor for erlotinib adverse events. Erlotinib might be used with careful monitoring of adverse events in patients with ABCB1 polymorphic variants.

We demonstrate the crystallization of thermally deposited amorphous germanium (Ge) microstrips on single layer graphene (SLG) by rapid melting growth. Lateral growth of large grain crystalline Ge was successfully obtained over entire microstrip structure. SLG has shown its capability to suppress the spontaneous nucleation in the melting Ge, where no or less intermixing of C and Ge atoms has been detected. The interaction of C atoms from the graphene and Ge atoms at the interface is the possible reason for the observation of large compressive strain generated in the Ge strip grown on SLG. This technique provides an innovative breakthrough towards the realization of single-crystalline Ge-on-insulator (GOI) structure on SLG to facilitate the next-generation ultra-large-scale integrated circuits (ULSIs) with multifunctionalities.

5-fluorouracil (5-FU) is part of the standard care for cancer treatment but is associated with high incidences of appetite loss and reduced food intake, which may contribute to chemotherapy-induced cachexia (weakness and wasting of tissue). The role of gastrointestinal satiety hormones in chemotherapy-induced appetite loss has not been intensively investigated. Peptide YY (PYY) and glucagon-like peptide (GLP)-1 are important signals of gastrointestinal satiety, so this study examined the roles of these gut hormones in 5-FU-induced reduction of dietary intake. Mice were given 5-FU (50 mg/kg, intraperitoneal [i.p.]) every day for 4 consecutive days. Gene expression levels of proglucagon (Pro-Gcg), a precursor of GLP-1, and PYY in the colon were examined by real-time RT-PCR. Serum levels of GLP-1 and PYY were measured by enzyme-linked immunosorbent assay. Some mice were pretreated with the GLP-1 receptor antagonist exendin9-39 (1 mg/kg) or the neuropeptide Y type 2 (NPY2) receptor antagonist BIIE0246 (2 mg/kg) via the i.p. route 30 minutes before 5-FU administration. Mice receiving 5-FU exhibited a significant reduction in food intake that was correlated with body weight loss. These mice also showed significantly enhanced expression levels of mRNAs encoding pro-GLP-1 and PYY in the transverse and distal colon as well as elevated serum concentrations of GLP-1 and PYY compared to vehicle-treated controls. The 5-FU-induced reduction in food intake was attenuated by BIIE0246 but not by exendin9-39. These data suggest that administration of a NPY2 receptor antagonist may be effective for attenuating the anorexia caused by 5-FU chemotherapy.

We demonstrate the crystallization of the microstrips of electrodeposited amorphous germanium (Ge) on graphene on insulator by rapid melting growth for the first time. Growth of single-crystalline Ge microstrips with (111) orientation was confirmed. The high level of compressive strain was found to be resulted from the intermixing of C atoms from multilayer graphene (MLG) and Ge. Probably the introduction of local C atom into Ge film enhances nucleation of Ge on MLG, which results in (111)-oriented Ge nuclei. Subsequent lateral growth enables crystallization of Ge with (111) orientation on the entire microstrip. The results also indicate that graphene is very useful to suppress the spontaneous nucleation in the melting Ge films and the lattice rotation or misorientation. This novel and innovative technique provides a breakthrough towards the realization of high quality Ge-on-insulator structures to facilitate the next-generation ultra-large-scale integrated circuits (ULSIs) with multifunctionalities.

Cisplatin, a platinum-based anti-cancer drug, is one of the most effective broad-spectrum anti-cancer agents used against various cancers. It has been recently suggested that low skeletal muscle mass is predictive of mortality in patients with cancer. Although several molecules produced by the actual tumor itself contribute to skeletal muscle impairment, we recently suggested that the administration of cisplatin could increase levels of muscle RING finger-1 (MuRF1) and atrogin-1, possibly leading to muscle atrophy in the mouse. Exercise is an important factor that induces muscle protein synthesis and muscle hypertrophy by enhancing the positive effects of the Akt/mTOR/p70S6 kinase pathway. In the present study, we therefore investigated the effect of treadmill exercise on cisplatin-induced muscle atrophy. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for four consecutive days. On day 4, the quadriceps and gastrocnemius muscles were isolated from the mice. The animals in the treadmill exercise groups were forced to run on a motorized treadmill for 20 min once a day for 9 days. In addition to muscle mass, the decrease in myofiber diameter associated with cisplatin administration was significantly restored by treadmill exercise. This exercise also significantly attenuated cisplatin-induced upregulation of MuRF1 and atrogin-1 in quadriceps and gastrocnemius muscle. The decreased Akt, p70S6 kinase, and Foxo3a phosphorylation observed with cisplatin treatment was significantly recovered by treadmill exercise in both the muscles. In the present study, myostatin (Mstn) gene expression, upregulated by cisplatin administration, was also attenuated by treadmill exercise. These findings suggest that treadmill exercise could attenuate cisplatin-induced muscle atrophy, at least partially, and could improve prognosis.

Aims: We analyzed the association of ABCB1 polymorphisms with erlotinib-induced toxicity and the pharmacokinetics in patients with non-small-cell lung cancer. Materials & methods: After erlotinib 150 mg was administered to 50 patients, ABCB1 polymorphisms were analyzed via either TaqMan® assays or direct nucleotide sequencing. Plasma concentrations were measured by HPLC. Results: The trough concentration at steady state in patients with the ABCB1 1236TT–2677TT–3435TT genotype was higher compared with others groups (p = 0.021) and patients carrying this genotype had a higher risk of developing higher grade 2 toxicity (p = 0.012). Conclusion: The present study suggested that the ABCB1 1236TT–2677TT–3435TT genotype was associated with higher plasma concentration and the risk of developing higher toxicity in patients treated with erlotinib. Original submitted 5 August 2011; Revision submitted 30 November 2011

To realize the advanced thin-film transistors (TFTs), high-carrier-mobility semiconductor films on insulator structures should be fabricated with low-temperature processing conditions (≤500 °C). To achieve this, we investigated the solid-phase crystallization of amorphous-GeSn films on insulating substrates under a wide range of Sn concentrations (0%–20%), film thicknesses (30–500 nm), and annealing temperatures (380–500 °C). Our results reveal that a Sn concentration close to the solid solubility of Sn in Ge (∼2%) is effective in increasing the grain-size of poly-GeSn. In addition, we discovered that the carrier mobility depends on the film thickness, where the mobilities are determined by the counterbalance between two different carrier scattering mechanisms. Here, vacancy-related defects dominate the carrier scattering near the insulating substrates (≤∼120 nm), and grain-size determined by bulk nucleation dominates the grain-boundary scattering of thick films (≥∼200 nm). Consequently, we obtained the m...

Although recommender systems have come to give recommendations with high precision, users are not always satisfied with the recommendations. User satisfaction is apparently influenced by many other factors. We specifically examined user intervention as one factor influencing user satisfaction. We tested two hypotheses: user intervention itself improves user satisfaction; and the more users intervene in the recommendation process, the more they are satisfied with the recommendations. We conducted an experiment incorporating user intervention of several kinds to reveal the relation between user intervention and user satisfaction.

Introduction: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor, a 150 mg daily dose of which has been shown to be effective for improving overall survival in non-small-cell lung cancer (NSCLC) patients who had failed at least 1 prior chemotherapy regimen. Furthermore, erlotinib demonstrated significant prolongation of progression-free survival versus standard chemotherapy in EGFR mutation positive NSCLC patients. However, skin rash and diarrhea often occurs, and these toxicities lead to discontinuation of therapy or dose reduction in many patients. Several population pharmacokinetics (PK) analyses have reported large interindividual variabilities in erlotinib blood exposure and its toxicities. However, none of those analyses clearly explains the determinants of these large interindividual variabilities. Here, aiming to develop a dose regimen that would maintain the clinical benefits of erlotinib while minimizing its adverse effects, we analyzed single nucleotide polymorphisms (SNPs) of PK-related genes and investigated the relationships between genotypes and interindividual variabilities in the PK and adverse effects. Methods: We performed a multicenter study of 50 patients treated with 150 mg erlotinib as a second-line or later treatment. PK and toxicity were assessed. For PK analyses, blood samples were collected from 28 patients at 5 to 18 time points, and trough blood samples were collected from 20 patients at 1 time point. SNPs in genes encoding metabolizing enzymes or efflux transporters (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, GSTT1, ABCB1, and ABCG2) were analyzed. Population PK analyses were carried out using NONMEM. SNPs were tested as covariates in a population PK model. The effects of these SNPs and erlotinib exposure on toxicity were evaluated. Results and Discussion: A 2-compartment model with first order absorption and linear elimination described the erlotinib PK. Only the ABCB1 1236C>T polymorphism was a statically significant covariate for CL/F, showing a 29.4% decrease in CL/F for the TT genotype as compared with the CC and the CT genotypes. The interindividual variability in CL/F decreased by 10.6% after inclusion of the TT genotype as a covariate in the model. This result indicates that a dose reduction to 100 mg for the TT genotype group could equalize the erlotinib exposure between each genotype group. A higher incidence of adverse effects (mainly diarrhea) was observed in the TT genotype group. Conclusions: Of the 20 SNPs that are related to erlotinib PK, only ABCB1 1236C>T influenced the exposure of erlotinib. This SNP was suggested to be related to the risk of adverse events. Individual dosing based on ABCB1 genotype might reduce the adverse effects. Further clinical trials are needed to investigate the toxicity and the clinical outcome of this dose regimen. Citation Format: Chihiro Endo-Tsukude, Ji-ichiro Sasaki, Sho Saeki, Norihiro Iwamoto, Megumi Inaba, Sunao Ushijima, Hiroto Kishi, Shinji Fujii, Hiroshi Semba, Kosuke Kashiwabara, Yukari Tsubata, Yuki Kai, Hideyuki Saito, Takeshi Isobe, Hirotsugu Kohrogi, Akinobu Hamada. Effect of genetic polymorphisms on erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5481. doi:10.1158/1538-7445.AM2015-5481

Solid-phase crystallization (SPC) of amorphous-GeSn (a-GeSn) films on insulating substrates has been developed combining with laser-annealed seeding, to realize next generation thin-film devices. By this technique, we have realized crystallization of GeSn (>10%) at low temperatures (~180oC), which is applicable for flexible thin-film devices on low cost plastic substrates with low softening temperatures (~200oC). In addition, the starting point of crystallization can be controlled by seeding, which is big advantage in device designing. Introduction In order to realize next generation flexible devices, novel functional materials have to be crystallized at controlled positions on insulating substrates below the softening temperature of low cost plastic substrates (~200oC). GeSn is attracting material for this purpose, since GeSn has higher carrier mobility than Si or Ge, and moreover, GeSn shows direct band structure by introducing substitutional Sn concentration more than 8%. Under such background, we have investigated solid-phase crystallization (SPC) of GeSn [1] and realized growth of GeSn at 180oC. However, to initiate the SPC at controlled positions, the samples have to be annealed above the melting point of Sn (~232oC) to form seeding regions, which is not applicable on flexible plastic substrates. In line with this, we propose an idea to use laser-annealing (LA) to form crystal seeds. By forming seeds by LA, lateral SPC is expected at process temperature below 200°C. Moreover, by decreasing the process temperature, we can expect that GeSn crystals with high substitutional Sn concentration should be obtained. Experimental Procedure In the experiment, amorphous Ge0.8Sn0.2 layers (100 nm thickness) were deposited on quartz substrates by a molecular beam technique. The samples were irradiated with a KrF excimer laser (wavelength: 248 nm, energy: 160 mJ/cm2) with 100 pulses in 1 sec to form seed regions, followed by thermal annealing (180 - 220 oC) for lateral SPC as shown in Fig. 1. Results and Discussion Nomarski images of samples as LA and after annealing at 180oC for 48h are shown in Figs. 2(a) and 2(b), respectively. The laser annealed seed region is formed as shown in Fig. 2(a). From the seed, a bright region spreads after 180oC annealing. The Raman spectra obtained at points A, B, and C in Figs. 2(a) and 2(b) are shown in Fig. 2(c). From these spectra, we can clearly say that lateral SPC is initiated from only the seed and no spontaneous nucleation occurs. From the length of lateral SPC region, growth rates of GeSn at various annealing temperatures (180, 200, 220 oC) are evaluated. It is found that the growth rate is about 1 μm/h at 180 oC, which is nearly 106 time as large as that of Ge [2]. The activation energy of the growth rate of Ge0.8Sn0.2 was estimated to be ~1.5 eV, which was smaller than that of Ge (~2.0 eV). This is attributed to the weakening atomic bonds by Sn atoms. This is a very useful technique to realize next generation flexible thin-film devices. Substitutional Sn concentration in grown layer obtained after annealing at 180oC for 48h is evaluated by Raman measurement, which is shown in Fig. 3. Substitutional Sn concentration in SPC region shows higher value (>10%) than that of LA region (~7.5%), which is attributed to difference of non-equilibrium conditions between SPC and LA. Interestingly, substitutional Sn concentration shows very high values exceeding 15% near the growth edge. The Sn concentration decreases with increasing distance from the edge. Decrease in the Sn concentration from >15% to ~10% is attributed to the post annealing effect of grown regions. Detailed physics will be discussed at the presentation. References [1] H. Chikita, et al., Appl. Phys. Lett. 105 (2014) 202112. [2] K. Toko, et al., Appl. Phys. Lett. 94 (2009) 192106. Figure 1

To produce high-performance devices on flexible plastic substrates, it is essential to form Ge-based group IV semiconductors on insulating substrates at low temperatures (≤250 °C). We have developed a technique for solid phase crystallization of amorphous GeSn (≤220 °C) enhanced by Sn doping, and combined with a seeding technique induced by Sn melting (∼250 °C). This combination produces lateral crystallization of amorphous GeSn from seed arrays with no incubation time. As a result, extremely high growth velocities at 220 °C, depending on Sn concentration, e.g., 0.13 μm/h (14% Sn) and 1100 μm/h (23% Sn), are achieved. These velocities are 104–108 times higher than that of pure Ge. This technique enables growth of crystalline GeSn island arrays (diameters: 50–150 μm) at low temperatures (≤250 °C) at controlled positions on insulating substrates.

e13072 Background: Erlotinib is metabolized by cytochrome P450 enzymes to form a para-hydroxyaniline metabolite that is further metabolized to quinone-imine. Erlotinib is detoxified when it conjugates with sulfate or glucuronide. We recently demonstrated that patients who experienced severe erlotinib-induced hepatotoxicity had higher metabolic ratios of glucuronides than those who developed moderate toxicity; this finding indicates that glucuronidation could be saturated and high levels of reactive metabolites might be trigger of glutathione (GSH) depletion. Ophthalmic acid (OA), which is an analog of GSH, may be a useful biomarker for hepatotoxicity because it is a sensitive indicator of GSH depletion in animal model. GSH acts as an enzyme-catalyzed antioxidant when cells and organisms experience electrophilic stress that arises from metabolic processes. Here, we examined the association between plasma concentration of OA and hepatotoxicity in patients who were treated with erlotinib in Japanese patients. Methods: We assessed data from 26 patients with NSCLC who each received a 150 mg dose of erlotinib. Plasma concentrations of OA and erlotinib were measured at before treatment using the liquid chromatography-quadrupole mass spectrometer system. Results: All 26 patients experienced one or more erlotinib-induced adverse events. The most frequent erlotinib-induced adverse events were mild to moderate skin rashes and diarrhea. There seemed to be a relationship between the plasma concentration of erlotinib and the grades of skin rashes and diarrhea. Interestingly, OA was detected only in one patient who developed grade 4 hepatotoxicity, indicating that this patient, who had a higher level of OA (36.9 ng/mL) in plasma. In contrast, the other 25 patients, who did not develop hepatotoxicity, had no detectable OA in plasma. Thus, the plasma concentration of OA was not related to the plasma concentration of erlotinib nor to the grade of skin rash. Conclusions: OA might be useful as a predictive biomarker of hepatotoxicity if measured before starting erlotinib treatment. Larger studies are needed to investigate the association between OA levels and the development of severe hepatotoxicity.

2593 Background: Erlotinib is an orally available, selective inhibitor of EGFR tyrosine kinase activity used in the treatment of patients with non-small cell lung cancer (NSCLC), and skin rash is a...

Background: Erlotinib is a selective inhibitor of EGFR tyrosine kinase activity used for the treatment of patients with NSCLC. It has been reported that ABCB1 polymorphisms affect pharmacokinetics and adverse events of erlotinib in Japanese patients (Hamada A, 2009 AACR meeting). Erlotinib is metabolized by CYP3A4, CYP3A5, CYP1A1, and CYP1A2. The purpose of this study was to investigate the association of CYP1A1 and CYP1A5 single nucleotide polymorphisms (SNPs) with inter-individual variability of erlotinib pharmacokinetics. Methods: Patients with NSCLC were treated with single-agent oral erlotinib 150 mg/day. Plasma levels of erlotinib were measured by high-performance liquid chromatography on days 1 and at steady state (>day 8). DNA was obtained from whole blood, and genotyping was carried out using an Applied Biosystems TaqMan SNP Genotyping Assay on an ABI PRISM® 7900HT system. Results: Fifty patients (mean age, 67 years) were enrolled in the study. Histological classifications were: adenocarcinoma (n=41), squamous cell carcinoma (n=7), and unknown (n=2). Smoking history was indicated as: never smoker (n=23), former smoker (n=24), and current smoker (n=3). For the CYP3A5 6986A>G polymorphism, the frequencies of wild-type (AA), heterozygote (GA), and homozygote (GG) were 6%, 34%, and 60%, respectively. For the CYP1A1 2455A>G polymorphism, the frequencies of wild-type (AA), heterozygote (GA), and homozygote (GG) were 64%, 24%, and 12%, respectively. The mean (±SD) maximum concentrations (Cmax), trough concentrations (Ctrough) on day 1, and steady-state trough concentrations (Css) on >day 8 were 1.66±0.73 μg/mL, 0.77±0.5 μg/mL, and 1.5±0.8 μg/mL, respectively. Lower exposure levels of erlotinib were observed in patients carrying the CYP3A5 6986AA allele than in patients carrying one or two G alleles (GA, GG). The Cmax on day 1 in patients carrying the CYP3A5 AA and GA/GG alleles were 0.76±0.27 μg/mL and 1.78±0.69 μg/mL, respectively. (p=0.0198) On the other hand, patients carrying the CYP1A1 2455GG allele had higher Css than in patients carrying the CYP1A1 2455AA or the CYP1A1 2455GA alleles (2.3±1.16 μg/mL vs. 1.4±0.69 μg/mL, p=0.0161) Conclusion: These results suggested that the CYP3A5 6986A>G and CYP1A1 2455A>G polymorphisms affect the pharmacokinetics of erlotinib in Japanese patients. Further studies involving a larger sample size will be required to evaluate whether measurement of the CYP3A5 and the CYP1A1 polymorphisms may help to optimize erlotinib treatment in individual patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5459. doi:10.1158/1538-7445.AM2011-5459