Explore the vast range of titles available.

In this study, 2/1 and 1/1 approximants in a quaternary Al–Pd–Au–Yb system were synthesized by substituting Au into original Al–Pd–Yb quasicrystals. In the Al 50 Pd 24 Au 10 Yb 16 and Al 52 Pd 22 Au 10 Yb 16 alloys, 2/1 and 1/1 phases were formed, respectively, and the lattice constants were relatively small—2.314 and 1.431 nm for the 2/1 and 1/1 phases, respectively. Scanning transmission electron microscopy revealed that both approximants comprise Tsai-type atomic clusters. Inverse magnetic susceptibility for the approximants obeyed the Curie–Weiss law, indicating the presence of paramagnetism. The effective magnetic moments were estimated to be 3.20 μB and 2.94 μB for the 2/1 and 1/1 phases, respectively, indicating that Yb in both approximants adopts an intermediate valence state.

Background:The importance of the role of ACPA in the pathogenesis of rheumatoid arthritis has been reported. ABT is a biologic DMARD that inhibits T-cell activation, and its efficacy is higher in ACPA-positive patients. However, it remains unclear which patients with positive autoantibodies to specific citrullinated proteins are particularly likely to benefit from ABT.Objectives:We designed a prospective 2-year observational follow-up study (ORIJIN study) of bDMARDs-naïve Japanese rheumatoid arthritis patients newly started subcutaneous ABT injections. This study was planned to analyze the association between clinical information and antigen-specific ACPA expression profiles in patients who responded to ABT.Methods:Patients with active rheumatoid arthritis inadequately respond to at least one csDMARD and decided to start subcutaneous ABA as a first bDMARD were eligible for observation. A total of 92 patients from six hospitals were enrolled in this observational study in the period of December 2016 to November 2020. The Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Disease Activity Score with 28-joint count C-reactive protein (DAS28-CRP), and DAS28 erythrocyte sedimentation rate (DAS28-ESR). Responders were defined as achieving low disease activity or remission measured by SDAI at 12 or 24 months Human leukocyte antigen (HLA) genotype was examined with written informed consent. Antigen-specific ACPA was investigated for 13 citrullinated peptides (Apolipoprotein E, Biglycan, 2 kinds of Clusterin, Enolase, 4 kinds of Fibrinogen A, Filaggrin, 2 kinds of Histone(H2A/a 1-20, H2B/a 62-81), and Vimentin) using a custom multiplex bead array (MagPlexTM). The fluorescence intensity was measured using the Luminex® System.Results:The SDAI remission rates after ABT in 92 patients were 22.8% and 29.3% at 12 and 24 months, respectively, and the rates of achieving low disease activity (SDAI≦11) were 64.1% and 74.7% at 12 and 24 months, respectively. The continuation rates of ABT at 12 and 24 months were 84.8% and 65.2%, respectively.Antibody titers against citrullinated fibrinogen (FibrinogenA_211_230) at 12 and 24 months in the group achieving low disease activity or below (364.7±585.2, 249.6±308.1) compared with the non-remission group (961.1±1330.7, 1074±1423.1), It was significantly lower than before treatment (p<0.05, Wilcoxon signed rank test).Conclusion:The antibody titer against citrullinated fibrinogen may be related to the therapeutic effect of ABT. Further investigation is required in the future.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Makio Kusaoi Asahi Kasei Medical Co.,Ltd, Asahi Kasei pharma Co.,Ltd, Bristol-Myers Squibb(BMS), Chugai Pharmaceutical Co.,Ltd, Goh Murayama: None declared, Takanori Azuma: None declared, Shintaro Hirata AbbVie/Abbott, Asahi-Kasei Pharma, Astellas, Ayumi, Bristol-Myers Squibb(BMS), Chugai Pharmaceutical Co.,Ltd, Eisai Co.,Ltd, Eli Lilly, Gilead, GlaxoSmithKlein(GSK), janssen, kyorin, Novartis, Pfizer, Sanofi, Tanabe-Misubishi, UCB, AbbVie/Abbott, Asahi-Kasei Pharma, Ayumi, Chugai Pharmaceutical Co.,Ltd, Eisai Co.,Ltd, Eli Lilly, Otsuka, Pfizer, Sanofi, Shionogi, Tanabe-Misubishi, UCB, Nobunori Takahashi AbbVie/Abbott, Astellas Pharma Inc, Bristol-Myers Squibb(BMS), Chugai Pharmaceutical Co.,Ltd, Eisai Co.,Ltd, Eli Lilly, janssen Pharmaceutical KK., Pfizer Japan, Tanabe-Misubishi, UCB, Akiko Mitsuo: None declared, Yoshiyuki Abe: None declared, Kentaro Minowa: None declared, Toshio Kawamoto: None declared, Akira Katagiri: None declared, Masakazu Matsushita: None declared, Kurisu Tada: None declared, Michihiro Ogasawara: None declared, Hirofumi Amano: None declared, Shinji Morimoto: None declared, Ken Yamaji Asahi Kasei Medical Co.,Ltd, Asahi Kasei pharma Co.,Ltd, Bristol-Myers Squibb(BMS), Chugai Pharmaceutical Co.,Ltd, Naoto Tamura AbbVie/Abbott, Bristol-Myers Squibb(BMS), Chugai Pharmaceutical Co.,Ltd, Eisai Co.,Ltd, Eli Lilly, GlaxoSmithKlein(GSK), janssen, Mitsubisi Tanabe Pharma Corporation, Novartis.

Background: The aim of this study was to investigate the patterns of epidermal growth factor receptor (EGFR) overexpression, EGFR gene amplification, and the presence of activating mutations in the tyrosine kinase domain of this gene in squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas of the uterine cervix. Methods: The EGFR expression, amplification, and mutation in cervical carcinomas were assessed by immunohistochemistry, fluorescence in situ hybridisation, and PCR–SSCP, respectively, and correlated with clinical data collected by a retrospective chart review. A functional assessment was performed by inactivating EGFR in cervical cancer cells with the potent inhibitor AG1478. Results: Immunohistochemical analysis revealed that 6 out of 59 (10.2%) cervical squamous cell carcinomas showed significant amplification of the EGFR locus, whereas none of the 52 adeno/adenosquamous cell carcinomas had detectable EGFR amplification ( P <0.05). The EGFR amplification significantly correlated with shorter overall survival ( P =0.001) in cervical squamous cell carcinomas. Multivariate analysis showed that EGFR gene amplification was an independent prognostic factor for overall survival ( P =0.011). None of the squamous cell carcinomas (0%: 0 out of 32) had detectable oncogenic mutations in EGFR exons 18 through 21. The frequencies of KRAS and BRAF mutations were very low in both squamous and adeno/adenosquamous cell carcinomas. Sensitivity of cervical cancer cells to AG1478 depended on the presence of EGFR overexpression. AG1478-induced EGFR inactivation in cell lines with EGFR overexpression significantly suppressed tumour development and progression in a mouse xenograft model. Conclusion: Our data suggest that EGFR signalling is important in a subset of cervical squamous cell carcinomas and that anti-EGFR therapy may benefit patients who carry the 7p11.2 amplicon in their tumours.

This study examined the status of KRAS and BRAF mutations, in relation to extracellular signal-regulated protein kinase (ERK) activation in 58 ovarian carcinomas to clarify the clinicopathological and prognostic significance of KRAS/BRAF mutations. Somatic mutations of either KRAS or BRAF were identified in 12 (20.6%) out of 58 ovarian carcinomas. The frequency of KRAS/BRAF mutations in conventional serous high-grade carcinomas (4.0% : 1/25) was significantly lower than that in the other histological type (32.3% : 10/31). Phosphorylated ERK1/2 (p-ERK1/2) expression was identified in 18 (38.2%) out of 45 ovarian carcinomas. KRAS/BRAF mutation was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage I, II ( P <0.001), and p-ERK1/2 ( P <0.001). No significant correlations between KRAS/BRAF mutations or p-ERK1/2 expression and overall survival were found in patients with ovarian carcinoma treated with platinum and taxane chemotherapy ( P =0.2460, P =0.9339, respectively). Next, to clarify the roles of ERK1/2 activation in ovarian cancers harbouring KRAS or BRAF mutations, we inactivated ERK1/2 in ovarian cancer cells using CI-1040. Cl-1040 is a compound that selectively inhibits MAP kinase kinase (MEK), an upstream regulator of ERK1/2, and thus prevents ERK1/2 activation. Profound growth inhibition and apoptosis were observed in CI-1040-treated cancer cells with mutations in either KRAS or BRAF in comparison with the ovarian cancer cells containing wild-type sequences. This was evident in both in vitro and in vivo studies. The findings in this study indicate that an activated ERK1/2 pathway is critical to tumour growth and survival of ovarian cancers with KRAS or BRAF mutations. Furthermore, they suggest that the CI-1040-induced phenotypes depend on the mutational status of KRAS and BRAF in ovarian cancers. Therefore, ovarian cancer patients with KRAS or BRAF mutations may benefit from CI-1040 treatment.

OBJECTIVE: To examine associations between rate of eating and macronutrient and dietary fiber intake, and body mass index (BMI). DESIGN: Cross-sectional study. SUBJECTS: A total of 1695 18-y-old female Japanese dietetic students. MEASUREMENTS: Macronutrient intake (protein, carbohydrate, and fat) and dietary fiber intake were assessed over a 1-month period with a validated, self-administered, diet history questionnaire. Body height and weight and rate of eating (according to five categories) were self-reported. RESULTS: Among the nutrients examined, only dietary fiber intake weakly, but significantly, and negatively correlated with BMI in a multiple regression analysis. The rate of eating showed a significant and positive correlation with BMI. The mean BMI was higher by 2.2, 1.5, 1.0, and 0.5 kg/m(2) in the 'very fast', 'relatively fast', 'medium', and 'relatively slow' groups, respectively, compared with the 'very slow' rate of eating group. This correlation remained evident after adjustment for nutrient intake. CONCLUSIONS: Rate of eating showed a significant and positive correlation with BMI, whereas only dietary fiber intake showed a weak correlation with BMI.

Background: This study examined the clinical significance of NAC1 and the expression level of its potential downstream target fatty acid synthase (FASN) in ovarian clear cell carcinomas (OCCCs), and evaluated the NAC1/FASN pathway as a potential therapeutic target. Methods: NAC1 and FASN expression and NACC1 gene amplification were assessed in ovarian cancers by immunohistochemistry, fluorescence in situ hybridisation, and clinical data collected by a retrospective chart review. C75, a FASN inhibitor, was used to assess whether this pathway represented a therapeutic target in OCCC. Results: High NAC1 expression was most frequent in clear cell tumours (40.0%:24/60). NACC1 gene amplification was identified in none of the 58 OCCCs. The frequency of NACC1 gene amplification was significantly higher in the high-grade serous histology than in the clear cell histology ( P <0.01). NAC1 expression was significantly correlated with FASN expression in both OCCC samples and OCCC cell lines. Either high NAC1 expression or high FASN expression significantly correlated with shorter progression-free and overall survival ( P =0.002 and 0.0048). NAC1 overexpression stimulated FASN expression, and NAC1 silencing using siRNA decreased FASN expression in OCCC cell lines. Profound growth inhibition was observed in C75-treated carcinoma cells with FASN overexpression when compared with the response in carcinoma cells without FASN expression. Conclusion: These findings indicate that NAC1/FASN overexpression is critical to the growth and survival of a subset of OCCC. The FASN silencing by the C75-induced phenotypes depends on the expression status of the targeted cell line. Therefore, NAC1/FASN pathway-targeted therapy may benefit selected OCCC patients.

BackgroundThis study evaluated the efficacy and safety of avacopan versus a prednisone taper in the subgroup of patients with antineutrophil cytoplasmic antibody-associated vasculitis (granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)) receiving cyclophosphamide (CYC) followed by azathioprine (or mycophenolate mofetil) in the ADVOCATE trial.MethodsKey efficacy outcomes were remission at week 26 and sustained remission at week 52. Additional outcomes included glucocorticoid toxicity, estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR) and safety.ResultsOf 330 patients receiving study medication, 116 (35.2%) received CYC (avacopan group, n=59; prednisone taper group, n=57). Remission at week 26 and sustained remission at week 52 were achieved by 37/59 (62.7%) and 33/59 (55.9%) patients in the avacopan group and 34/57 (59.6%) and 30/57 (52.6%) in the prednisone taper group, respectively. Over 52 weeks, relapses were observed in 13.0% in the avacopan group and 22.6% in the prednisone taper group. Improvement in eGFR, speed of albuminuria reduction and differences in glucocorticoid toxicity favoured the avacopan group. Serious adverse events occurred in 55.9% and 56.1% of patients in the avacopan and prednisone taper groups, respectively.ConclusionsThis subgroup analysis of patients who received CYC shows similar rates of remission in the avacopan and prednisone taper groups. Compared with the prednisone taper regimen, the avacopan regimen was associated with a numerically lower relapse rate, greater improvement in eGFR, faster reduction in UACR, lower glucocorticoid-related toxicity and similar overall safety. These results support the use of avacopan in combination with CYC to treat GPA or MPA.Trial registration numberNCT02994927.

We retrospectively investigated the efficacy and feasibility of concurrent chemoradiotherapy for patients with severe dysphagia caused by oesophageal squamous cell carcinoma. Concurrent chemoradiotherapy was performed in 57 patients with T3 or T4 disease containing M1 lymph node (LYM) disease. Chemotherapy consisted of protracted infusion of 5-fluorouracil (5-FU) 400 mg m −2  24 h −1 on days 1–5 and 8–12, combined with 2-h infusion of cisplatin (CDDP) 40 mg m −2 on days 1 and 8. Radiation treatment at a dose of 30 Gy in 15 fractions of the mediastinum was administered concomitantly with chemotherapy. A course schedule with 3-week treatment and a 1 to 2-week break was applied twice, with a total radiation dose of 60 Gy, followed by two or more courses of 5-FU and CDDP. In all, 24 patients (42%) achieved a complete response, and the 3-year survival rate was 19%. Major toxicities were leukocytopenia and oesophagitis, and there were two (4%) treatment-related deaths. In contrast, 22 patients with T3 disease survived longer than 35 patients with T4 disease ( P =0.001); however, the survival rate in 15 patients with M1 LYM disease did not differ significantly from that in 42 patients without M1 LYM disease ( P =0.3545). Our results indicate that definitive chemoradiotherapy is potentially curative for locally advanced oesophageal carcinoma with malignant stricture. The efficacy and survival of patients treated with this regimen are related to the T factor.

Alkylating agents have strong leukemogenic potential. There are a number of recent acute myeloid leukemia (t-AML) cases related to previous paclitaxel exposure. These leukemias tend to be of aggressive subtypes with long-latency periods. Unlike previously reported cases, the present case was of the secondary acute megakaryoblastic myeloid leukemia (AML M7) subtype. Additionally, it did not harbor a translocation in chromosome 19. A 73-year-old woman was diagnosed with t-AML M7 with antecedent myelodysplasia. Leukemia followed a second induction of paclitaxel- and carboplatin-based chemotherapy for recurrent ovarian cancer. Her second induction began 25 months after completion of her first course of chemotherapy. The increased incidence of postpaclitaxel leukemia suggests a probable role for paclitaxel as a leukemogenic agent. It highlights the importance of assessing for leukemia risk factors prior to beginning paclitaxel therapy.

Mutations of the p53 gene are detected frequently in oesophageal dysplasia and cancer. It is unclear whether Lugol-unstained lesions (LULs) with non-dysplastic epithelium (NDE) are precursors of oesophageal squamous cell carcinoma (ESCC). To study the genetic alterations of NDE in the multistep process of oesophageal carcinogenesis, we determined the relationship between p53 mutations and LULs-NDE. Videoendoscopy with Lugol staining was performed prospectively in 542 oesophageal cancer-free subjects. Lugol-unstained lesions were detected in 103 subjects (19%). A total of 255 samples, including 152 LULs (NDE, 137; dysplasia, 15) and 103 paired samples of normal staining epithelium, were obtained from 103 subjects. After extraction of DNA and polymerase chain reaction analysis, direct sequencing method was applied to detect mutations of the p53 gene. The p53 mutation was detected in five of 137 samples with LULs-NDE (4%) and in five of 15 samples with dysplasia (33%). A hotspot mutation was found in 20% of LULs-NDE with p53 mutation and in 40% of dysplasia with p53 mutation. In contrast, no p53 mutations were found in 103 paired NDE samples with normal Lugol staining. In biopsy samples from oesophageal cancer-free individuals, the p53 missense mutations containing a hotspot mutation were found in NDE, which was identified as an LUL. These findings suggest that some LULs-NDE may represent the earliest state of oesophageal squamous cell carcinoma in Japanese individuals.