Aquaporin-11 (AQP11) is an intracellular AQP. Several studies with Aqp11-/- mice have shown that AQP11 has a role in normal development of the kidney after birth. Our previous studies have suggested that alteration of oxygen homeostasis may be involved in the kidney injury caused by AQP11 deficiency, although the underlying mechanism is largely unknown. To clarify this issue, we examined genes that are related to oxygen homeostasis in Aqp11-/- mice. Among 62 genes that are involved in oxygen homeostasis, 35 were upregulated by more than 2-fold in Aqp11-/- mice in comparison with wild-type mice. Pathway analysis using these genes extracted the pathway responsible for production of reactive oxygen species in macrophages. As expression of the genes involved in the NADPH oxidase 2 (NOX2) complex was dramatically increased by more than 14-fold, we further analyzed NOX2 at the protein level. Immunoblotting analysis demonstrated a dramatic increase of NOX2 protein in the kidney of Aqp11-/- mice, and immunohistochemistry showed that NOX2 protein and a marker protein for macrophages were increased in the renal interstitium. These results indicate that NOX2-induced oxidative stress accompanied by macrophage infiltration plays an important role in alteration of oxygen homeostasis in Aqp11-/- mice.
#6120 Background : Capecitabine and cyclophosphamide(XC) are shown to have a synergistic effect in the preclinical study and can be given orally with non-overlapping toxicities. Phase I study of XC was conducted for metastatic breast cancer patients and the recommended dose was 1657/mg/m2/day of X and 65mg/m2/day of C, respectively, which were to be given daily for 2 weeks at every 3-week schedule. We conducted phase II study with this regimen.
 Patients and methods: Women with advanced or metastatic breast cancer who had been treated previously with anthracyclines but not with taxanes, were entered into this trial. Other eligibility criteria included an age from 20 to 74 years, ECOG performance status 0-2, presence of measurable lesions according to the RECIST criteria, HER2-negative tumors, and acceptable major organ functions. One course of XC consisted of the above recommended dose and schedule, and at least 6 courses were to be given unless progression of the disease or unacceptable toxicities occurred. The primary endpoint was response rate and the secondary endpoints were progression free survival (PFS), overall survival (OS) and adverse events. The study was started in July 2005 and ended in December 2007.
 Results: Forty-eight patients were registered. The median age was 57 (range: 32 to 72). Thirty-three patients were postmenopausal. Estrogen and progesterone receptor was positive in 30 and 23 patients, negative in 14 and 19, and unknown in 4 and 6 patients, respectively. Three patients never received XC, and 2 patients were withdrawn from the study due to nausea and vomiting during the first course. Two patients were not evaluable for tumor response. Among 43 evaluable patients, there was complete response in 2 patients, partial response in 14, stable disease in 8, and progression of the disease in 19. Thus, an overall response rate was 87%. The response rate of metastatic lesions in each organ was 50% in lungs (6 patients), 65% in liver (17), 80% in lymph nodes (15), and 1.4% in skin (7), respectively. The median PFS and OS was 146 (85 to 942+) days and 672 days with a median follow-up time of 311 (97-1045+) days, respectively. Grade 3 toxicity was encountered for neutropenia with no fever in 5, anorexia in 2, and nausea/vomiting and diarrhea in 1 of each patient. Grade 1 and 2 hand-foot syndrome was experienced in 12 and 2 patients, respectively. One patient with liver metastasis showed grade 3 anemia, thrombocytopenia and elevated serum transaminase levels.
 Conclusion: Oral XC combination (1657/mg/m2/day and 65mg/m2/day for 2 weeks at every 3-week schedule) is effective to women with advanced or metastatic breast cancer with acceptable toxicities. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6120.
Highly purified beta-core fragment was obtained from urine of a pregnant woman with use of an immunoaffinity column. The amino acid sequence of beta-core fragment indicated that it is composed of two polypeptides linked by a disulfide bond. The two polypeptides correspond to the 6-40 and 55-92 portions of hCG beta-subunit. Both Asn13 and Asn30 residues were glycosylated. The N-linked sugar chains of beta-core fragment were quantitatively released as radioactive oligosaccharides by hydrazinolysis, followed by N-acetylation and NaB3H4 reduction. The radioactive oligosaccharides were fractionated by serial lectin column chromatography and Bio-Gel P-4 column chromatography, and their structures were investigated by sequential exoglycosidase digestion and periodate oxidation. The results indicated that they were a mixture of the four oligosaccharides: Man alpha 1----6(+/- Man alpha 1----3)Man beta 1----4GlcNAc beta 1----4(+/- Fuc alpha 1----6)GlcNAc. The structural characteristics of the sugar chains of beta-core fragment are quite different from those of the beta-subunit of hCG whose structures were typical biantennary sugar chains containing the Neu5Ac alpha 2----3Gal beta 1----4GlcNAc beta 1----2 group as their outer chains.
Background: Although superior antitumor activity of anastrozole over tamoxifen has been well established in postmenopausal breast cancer patients, it still remains to be examined whether or not anastrozole is superior to tamoxifen in premenopausal breast cancer patients whose ovarian function is suppressed by goserelin to postmenopausal levels. The aim of this study was to compare anastrozole plus goserelin versus tamoxifen plus goserelin as pre-operative treatment for premenopausal Japanese women with breast cancer. Methods: Phase III, randomized, double-blind, parallel-group, multi-center study (D539BC00001). Premenopausal patients (pts) with ER-positive and HER2-negative breast cancer and with operable and measurable lesions (T [2-5 cm], N0, M0) were randomized 1:1 to receive a goserelin 3.6 mg depot injection once monthly plus either anastrozole 1 mg (A+G) or tamoxifen 20 mg (T+G) p.o. once daily. Treatment continued for 24 weeks prior to surgery or until any other criterion for discontinuation was met. Concomitant chemotherapy was not permitted during the pre-operative period. The primary objective was to assess the best overall tumor response (either a complete response [CR] or a partial response [PR]), according to modified RECIST criteria. Tumor size was measured by caliper and ultrasound every 4 weeks and by magnetic resonance imaging/computed tomography (MRI/CT) every 12 weeks. Tolerability (adverse events [AEs], laboratory tests, vital signs, WHO performance status) was assessed as a secondary objective. AEs were evaluated according to CTCAE v3.0. Results: In total, 197 pts were randomized (A+G: 98, T+G: 99) and 185 pts completed the 24-week pre-operative treatment period and went on to receive breast surgery. The remaining 12 pts discontinued study treatment due to disease progression (A+G: 1; T+G: 5), voluntary discontinuation (A+G: 2; T+G: 3) and AE (T+G: 1). Pt demographics were generally well balanced. Median duration of exposure was similar for A+G (171 days) and T+G (170 days); treatment compliance was 99% for both. A+G led to a statistically significantly higher overall response rate compared with T+G, by caliper as well as by ultrasound and MRI/CT. The safety profiles were consistent with the known safety profile of anastrozole, tamoxifen and goserelin. The incidence of AEs was similar for A+G (88.8%) vs T+G (85.7%); most AEs were mild or moderate (CTC grade 1 or 2). The most common AEs were hot flash (A+G: 52.0%; T+G: 53.1%) and arthralgia (A+G: 35.7%; T+G: 20.4%). Conclusion: This study has demonstrated that the A+G combination has a superior benefit-risk profile compared with T+G as pre-operative treatment in Japanese premenopausal women with ER-positive breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-12-03.
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