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An, E.,Ock, C.-Y.,Kim, T.-Y.,Lee, K.-H.,Han, S.-W.,Im, S.-A.,Kim, T.-Y.,Liao, W.-L.,Cecchi, F.,Blackler, A.,Thyparambil, S.,Kim, W. H.,Burrows, J.,Hembrough, T.,Catenacci, D. V. T.,Oh, D.-Y.,Bang, Y.- KLUWER ACADEMIC PUBLISHERS GROUP 2017 Annals of Oncology Vol. No.
<P><B>Abstract</B></P><P><B>Background</B></P><P>A wide range of response rates have been reported in HER2-positive gastric cancer (GC) patients treated with trastuzumab. Other HER2-targeted therapies for GC have yet to show efficacy in clinical trials. These findings raise question about the ability of standard HER2 diagnostics to accurately distinguish between GC patients who would and would not benefit from anti-HER2 therapies.</P><P><B>Patients and methods</B></P><P>GC patients (<I>n </I>=<I> </I>237), including a subset from the Trastuzumab in GC (ToGA) trial were divided into three groups based on HER2 status and history of treatment with standard chemotherapy or chemotherapy plus trastuzumab. We applied mass spectrometry-based proteomic analysis to quantify HER2 protein expression in formalin-fixed tumor samples. Using HER2 expression as a continuous variable, we defined a predictive protein level cutoff to identify which patients would benefit from trastuzumab. We compared quantitated protein level with clinical outcome and HER2 status as determined by conventional HER2 diagnostics.</P><P><B>Results</B></P><P>Quantitative proteomics detected a 115-fold range of HER2 protein expression among patients diagnosed as HER2 positive by standard methods. A protein level of 1825 amol/µg was predicted to determine benefit from the addition of trastuzumab to chemotherapy. Trastuzumab treated patients with HER2 protein levels above this cutoff had twice the median overall survival (OS) of their counterparts below the cutoff (35.0 versus 17.5 months, <I>P </I>=<I> </I>0.011). Conversely, trastuzumab-treated patients with HER2 levels below the cutoff had outcomes similar to HER2-positive patients treated with chemotherapy. (Progression-free survival = 7.0 versus 6.5 months: <I>P </I>=<I> </I>0.504; OS = 17.5 versus 12.6 months: <I>P </I>=<I> </I>0.520). HER2 levels were not prognostic for response to chemotherapy.</P><P><B>Conclusions</B></P><P>Proteomic analysis of HER2 expression demonstrated a quantitative cutoff that improves selection of GC patients for trastuzumab as compared with current diagnostic methods.</P>
Allergenicity of two Anisakis simplex allergens evaluated in vivo using an experimental mouse model
Cho, M.K.,Park, M.K.,Kang, S.A.,Caballero, M.L.,Perez-Pinar, T.,Rodriguez-Perez, R.,Ock, M.S.,Cha, H.J.,Hong, Y.C.,Yu, H.S. Academic Press 2014 Experimental parasitology Vol.146 No.-
Anisakis (Anisakidae) is one of the most important causes of helminth-induced allergic reactions and elicits clinical responses that include urticaria, rhinitis, bronco-constriction, cough, and/or gastrointestinal symptoms. More than 13 reactive allergens have been identified in the serum of Anisakis allergy patients, but the allergenicity of only a few of these have been evaluated in vivo using a mouse model. To evaluate the allergenicity of two important allergens, Ani s 1 and Ani s 9, we induced experimental allergic airway inflammation in a mouse model by repeated intranasal administration of the allergens. Both recombinant proteins (rAni s 1 and rAni s 9) elicited increased airway hyperresponsivity, airway infiltration by inflammatory cells (especially eosinophils), bronchial epithelial cell hyperplasia, all of which are characteristic of allergic airway inflammation. These allergens significantly increased the levels of Th2-related cytokines (IL-4, IL-5, IL-13, and IL-25) and Th17 related cytokines (IL-6 and IL-17) in both splenocytes and airway (except IL-17 in airway by rAni s 9). OVA-specific IgE and total IgE were increased in rAni s 1 and rAni s 9 treated mice as compared with controls treated with OVA alone. In addition, these two allergens induced gene expression of thymic stromal lymphopoietin (TSLP) and IL-25 (initiators of the Th2 response), as well as CXCL1 (initiator of the Th17 response) in mouse lung epithelial cells. In conclusion, repeated intranasal treatments with rAni s 1 and rAni s 9 induced airway inflammation in mice by elevating of Th2 and Th17 responses in the lung.
Metabolic landscape of advanced gastric cancer according to HER2 and its prognostic implications
Ock, C. Y.,Kim, T. Y.,Lee, K. H.,Han, S. W.,Im, S. A.,Kim, T. Y.,Bang, Y. J.,Oh, D. Y. Springer Science + Business Media 2016 Gastric cancer Vol.19 No.2
<P>In advanced gastric cancer (AGC), HER2 is a validated therapeutic target. However, the metabolic landscape of AGC based on HER2 status has not been reported. Furthermore, the prognostic value of HER2 in AGC is under debate. The purpose of this study was to determine the metabolic landscape and prognosis on the basis of HER2 status in AGC. We analyzed 866 AGC patients treated with palliative chemotherapy and whose HER2 status was evaluated. HER2 positivity was defined as HER2 IHC 3+ or HER2/CEP17 ratio a parts per thousand yen2. Among them, 363 patients were evaluated with F-18 FDG-PET before chemotherapy. We analyzed mSUV (maximal standardized uptake value) according to HER2 status and clinical outcomes. Among 866 patients, 225 (26.0 %) had HER2+ GC. The mSUV of HER2+ GC was significantly higher than that of HER2- GC (12.6 vs. 8.7, p < 0.001). Increased HER2 IHC positivity was correlated with increased mSUV (IHC-: 8.1, IHC 1+: 8.2, 2+: 11.4, 3+: 13.2, p < 0.001). Excluding HER2+ patients who received HER2-targeting agents, OS of patients was not different by HER2 status (12.5 vs. 11.9 months, p = 0.688). However, according to tumor metabolism, patients with higher mSUV showed worse OS regardless of HER2 positivity (mSUV < 12.8:14.8, a parts per thousand yen12.8:8.6 months, p < 0.001). Tumor metabolism of AGC adversely influenced OS under treatment with cytotoxic chemotherapy. Tumor metabolism was higher in HER2+ AGC than HER2-. However, HER2 was not a prognostic factor in patients who received chemotherapy without HER2-targeting agents.</P>
Development and quality of porcine embryos in different culture system and embryo-producing methods
Ock, S-A.,Lee, S-L.,Kim, J-G.,Kumar, B-M.,Balasubramanian, S.,Choe, S-Y.,Rho, G-J. Cambridge University Press 2007 Zygote Vol.15 No.1
<B>SUMMARY</B><P>In this study, the developmental ability and cellular composition of porcine IVF, parthenote and somatic cell nuclear transfer (SCNT) embryos were evaluated following different <I>in vitro</I> culture systems. Group 1, embryos were cultured in NCSU-23 with 5.55 mM D-glucose (NCSU+) until day 6 on 20% O2 or 5% O2 (Group 2). Group 3, embryos were cultured in D-glucose-free NCSU-23 (NCSU−) with 0.17 mM Na pyruvate/2.73 mM Na lactate for 58 h and subsequently cultured in NCSU+ until day 6 (NCSU −/+) on 20% O2 or 5% O2 (Group 4). IVF blastocysts did not differ significantly with O2 concentrations, but differed significantly with major energy source (glucose and pyruvate/lactate). In Group 3 and 4 IVF blastocysts, the total cell number and apoptosis rates were not significantly different with different O2 concentrations. Blastocyst rate, total cell number and apoptosis rate in Groups 3 and 4 parthenote embryos also were not significantly different. Parthenote and SCNT, under the same culture treatment, exhibited significant differences in blastocyst and apoptosis rates (47.5 ± 16.1 vs. 24.0 ± 4.0 and 4.9 ± 9.0 vs. 22.8 ± 23.3). Apoptosis-generating rate increased in the order parthenote, IVF and then SCNT. In conclusion, <I>in vitro</I> development of porcine embryos was not affected by O2 concentrations but was affected by major energy source. Even so, the concentration of each major energy source and the timing of its inclusion in culture could accomplish relatively high embryonic development, the apoptosis rate stressed that more work still needs to be done in developing a better defined culture system that could support SCNT embryos equivalent to <I>in vivo</I> preimplantation porcine embryos.</P>
Ock, C. Y.,Oh, D. Y.,Lee, J.,Kim, T. Y.,Lee, K. H.,Han, S. W.,Im, S. A.,Kim, T. Y.,Bang, Y. J. Springer Science + Business Media 2016 Gastric cancer Vol.19 No.2
<P>Weight loss during chemotherapy is a significant prognostic factor for poor survival in patients with advanced gastric cancer (AGC). However, in most studies, weight loss was measured at the end of chemotherapy, limiting its clinical use. In this study, we evaluated whether weight loss during the first month of chemotherapy could predict survival outcomes in patients with AGC. We analyzed 719 patients with metastatic or recurrent AGC who were receiving palliative chemotherapy. We calculated the initial body mass index (BMIi), percent weight loss after 1 month of chemotherapy (Delta W (1)m), percent weight loss after last administration of chemotherapy (Delta W (end)), and average weight loss per month during chemotherapy (Delta W/m). We correlated these data with overall survival (OS) by receiver-operating characteristic (ROC) curves and Kaplan-Meier curves, and performed a subgroup analysis using Cox regression. The probabilities of longer OS had stronger correlations with Delta W/m and Delta W (1)m than with Delta W (end) or BMIi. A significant positive correlation between Delta W (1)m and Delta W/m (r (2) = 0.591, p < 0.001) was observed. Median OS of patients with Delta W (1)m more than 3 % was significantly shorter than in patients with less weight loss (OS: 9.7 vs. 16.3 months, p < 0.001). Subgroup analysis revealed that Delta W (1)m accompanied poor survival irrespective of other clinical characteristics. Weight loss at the very first month of palliative chemotherapy could predict unfavorable survival outcomes in AGC.</P>
Ock, C. Y.,Nam, A. R.,Lee, J.,Bang, J. H.,Lee, K. H.,Han, S. W.,Kim, T. Y.,Im, S. A.,Kim, T. Y.,Bang, Y. J. unknown 2017 GASTRIC CANCER Vol.20 No.2
<P>The NLR is a significant poor prognostic factor in advanced GC. The NLR is mainly associated with osteopontin and interleukin-6. Besides the NLR, SDF-1 is an independent poor prognostic factor in GC. Consideration of both the NLR and SDF-1 might give insights into antitumor immunity in GC.</P>
Ock, C. Y.,Nam, A. R.,Bang, J. H.,Kim, T. Y.,Lee, K. H.,Han, S. W.,Im, S. A.,Kim, T. Y.,Bang, Y. J.,Oh, D. Y. unknown 2017 GASTRIC CANCER Vol.20 No.1
<P>Serum CAF profiling differentiated GC patient groups. A high 11-CAF signature could identify GC patients with a poor prognosis when treated with standard chemotherapy who need urgent new treatment strategies.</P>