Heterodimerization of Glycosylated Insulin-Like Growth Factor-1 Receptors and Insulin Receptors in Cancer Cells Sensitive to Anti-IGF1R Antibody

Identification of predictive biomarkers is essential for the successful development of targeted therapy. Insulin-like growth factor 1 receptor (IGF1R) has been examined as a potential therapeutic target for various cancers. However, recent clinical trials showed that anti-IGF1R antibody and chemotherapy are not effective for treating lung cancer.In order to define biomarkers for predicting successful IGF1R targeted therapy, we evaluated the anti-proliferation effect of figitumumab (CP-751,871), a humanized anti-IGF1R antibody, against nine gastric and eight hepatocellular cancer cell lines. Out of 17 cancer cell lines, figitumumab effectively inhibited the growth of three cell lines (SNU719, HepG2, and SNU368), decreased p-AKT and p-STAT3 levels, and induced G 1 arrest in a dose-dependent manner. Interestingly, these cells showed co-overexpression and altered mobility of the IGF1R and insulin receptor (IR). Immunoprecipitaion (IP) assays and ELISA confirmed the presence of IGF1R/IR heterodimeric receptors in figitumumab-sensitive cells. Treatment with figitumumab led to the dissociation of IGF1-dependent heterodimeric receptors and inhibited tumor growth with decreased levels of heterodimeric receptors in a mouse xenograft model. We next found that both IGF1R and IR were N-linked glyosylated in figitumumab-sensitive cells. In particular, mass spectrometry showed that IGF1R had N-linked glycans at N913 in three figitumumab-sensitive cell lines. We observed that an absence of N-linked glycosylation at N913 led to a lack of membranous localization of IGF1R and figitumumab insensitivity.The data suggest that the level of N-linked glycosylated IGF1R/IR heterodimeric receptor is highly associated with sensitivity to anti-IGF1R antibody in cancer cells

Adaptive Change in Intra-Winter Distribution of Relatively Cold Events to East Asian Warming

For the past few decades, daily winter temperatures over East Asia have been higher and less variable. Generally, these simple temperature-distribution shifts should lead to a decrease in the occurrence of cold extremes, but observations of the changes in the extremes are often complicated. In the present study, the change in the occurrence of relatively cold events (daily temperature anomaly, _?T_n-2_ã_nfor that season) in each winter monsoon over East Asia was examined using ground observations of daily temperature for the period 1954 - 2006. The time-mean temperature for each winter was subtracted to remove the interannual variability and long-term trend. Our analyses reveal that the intraseasonal temperature distribution over East Asia has changed with a negative skew, and the frequency of the relatively cold events has slightly increased (by 0.09 days per decade) over the past few decades, on an average, for the entire analysis domain (east of 105°E, 122 stations). In particular, the increase occurs me dominantly (82% of the total stations) in regions north of 40°N where a stronger warming has progressed. The frequency of relatively cold events is found to be significantly correlated with the variance of the Siberian high and the mean of the Arc tic Oscillation. The increasing trend in the frequency of relatively cold events may serve to partly countervail the decrease (-1.12 days per decade) in the frequency of absolute cold events (daily temperature anomaly, _?T_n2_ã_noverall) across the entire observation period

Prognostic factors for Korean patients with anaplastic thyroid carcinoma

BACKGROUND: Anaplastic thyroid carcinoma (ATC), although rare, is one of the most aggressive human cancers, and patients with ATC have extremely poor prognoses despite various therapeutic measures. We wished to determine the prognostic factors of survival and effect of treatment on survival rate in patients with ATC. METHODS: We retrospectively reviewed the medical records of the 121 patients (41 men and 80 women) diagnosed with ATC from January 1995 to June 2004 at 5 major referral centers in Korea. RESULTS: Mean patient age at diagnosis was 64 +/- 11 years (range, 17-84 years). Of the 121 patients, 11 (9%) had intrathyroidal tumors, 69 (57%) had extrathyroidal tumors or lymph node involvement, 29 (24%) had distant metastases, and 12 had no data about staging (9%). The mean tumor diameter was 5.5 +/- 2.5 cm (range, 0.5-17.0 cm). At a median follow-up of 41 months (range, 26-122 months), 8 patients were alive. Median survival time was 5.1 months. The disease-specific survival rates were 42% at 6 months, 16% at 12 months, and 9% at 24 months. Sixteen patients (13%) received only supportive care, 25 (21%) received surgery alone, 20 (16%) received radiation treatment or chemotherapy without surgery, and 60 (50%) received surgery plus radiation treatment or chemotherapy. Multivariate analysis showed that age less than 60 years, tumor size less than 7 cm, and lesser extent of disease were independent predictors of lower disease-specific mortality. CONCLUSIONS: Long-term survival is possible for ATC patients less than 60 years old and with small localized tumors. Although aggressive multimodal therapy, including surgery, radiation treatment, and chemotherapy, was not significantly associated with improved survival, we advocate aggressive multimodal therapy in selected ATC patients with good prognostic factors