Somatic mutational analysis of FAK in breast cancer: a novel gain-of-function mutation due to deletion of exon 33.

Focal adhesion kinase (FAK) regulates cell adhesion, migration, proliferation, and survival. We identified a novel splicing mutant, FAK-Del33 (exon 33 deletion, KF437463), in both breast and thyroid cancers through colony sequencing. Considering the low proportion of mutant transcripts in samples, this mutation was detected by TaqMan-MGB probes based qPCR. In total, three in 21 paired breast tissues were identified with the FAK-Del33 mutation, and no mutations were found in the corresponding normal tissues. When introduced into a breast cell line through lentivirus infection, FAK-Del33 regulated cell motility and migration based on a wound healing assay. We demonstrated that the expression of Tyr397 (main auto-phosphorylation of FAK) was strongly increased in FAK-Del33 overexpressed breast tumor cells compared to wild-type following FAK/Src RTK signaling activation. These results suggest a novel and unique role of the FAK-Del33 mutation in FAK/Src signaling in breast cancer with significant implications for metastatic potential.

Rapid endogenic rock recycling in magmatic arcs.

In subduction zones, materials on Earth's surface can be transported to the deep crust or mantle, but the exact mechanisms and the nature of the recycled materials are not fully understood. Here, we report a set of migmatites from western Yangtze Block, China. These migmatites have similar bulk compositions as forearc sediments. Zircon age distributions and Hf-O isotopes indicate that the precursors of the sediments were predominantly derived from juvenile arc crust itself. Using phase equilibria modeling, we show that the sediments experienced high temperature-to-pressure ratio metamorphism and were most likely transported to deep arc crust by intracrustal thrust faults. By dating the magmatic zircon cores and overgrowth rims, we find that the entire rock cycle, from arc magmatism, to weathering at the surface, then to burial and remelting in the deep crust, took place within ~10 Myr. Our findings highlight thrust faults as an efficient recycling channel in compressional arcs and endogenic recycling as an important mechanism driving internal redistribution and differentiation of arc crust.

Focal adhesion kinase regulates the phosphorylation protein tyrosine phosphatase-α at Tyr789 in breast cancer cells.

Protein tyrosine phosphatase (PTP)­α regulates the phosphorylation of focal adhesion kinase (FAK), which is important in cellular signal transduction and integration of proteins. It has been demonstrated that a FAK­Del33 mutation (deletion of exon 33; KF437463) in breast cancer tissues regulates cell migration through FAK/Src signaling activation. However, the detailed pathway for Src activation with FAK­Del33 remains to be elucidated. The present study used a retroviral expression system to examine changes in PTPα phosphorylation affected by the FAK­Del33 protein in breast cancer cells. Small interfering (si)RNA targeting PTPα interfered with the phosphorylation of Src. Wound­healing and migration assays were performed to identify cell morphology and quantitative analysis was performed by examining band color depth in western blot analysis. Significant differences were observed in the phosphorylation level of PTPα at Tyr789 between the FAK­Del33 and the wild­type breast cancer cells, suggesting that FAK regulated the phosphorylation level of PTPα at Tyr789 in breast cancer mutant FAK­Del33 cells. The gene expression profile with FAK siRNA did not alter the levels of phosphorylation in other mutants, including autophosphorylation disability (Y397F), ATP kinase dominant negative (K454R) and protein 4.1, ezrin, radixin, moesin domain attenuate (Δ375). FAK RNAi inhibited the activity of the FAK­Del33 at the Src site and rescued the elevated cell migration and invasion. The present study demonstrated for the first time, to the best of our knowledge, an increase in the phosphorylation level of PTPα­Tyr789 by its upstream activator, FAK­Del33, leading to Src activation in certain breast cancer cells, which has significant implications for metastatic potential.

Validation of the Chinese version of the Subjective Global Assessment scale of nutritional status in a sample of patients with gastrointestinal cancer.

BACKGROUND AND AIMS: To verify the validity of the Subjective Global Assessment (SGA) on the nutritional assessment and prognosis prediction in Chinese patients with gastrointestinal cancer. METHODS: Five hundred and five patients with newly diagnosed gastrointestinal cancer who underwent surgeries were enrolled between August 2004 and August 2006. The sample consisted of 307 males (60.8%) and 198 females (39.2%). The nutritional status was assessed using SGA for each patient prior to operation. Simultaneously, anthropometric parameters and laboratory tests including serum albumin (ALB) and prealbumin (PA) levels were also obtained. The postoperative evaluation included length of stay, occurrence of complications, and in-hospital medical expenditures. RESULTS: Based on the results of preoperative SGA, the patients were classified into 3 groups: well nourished (group A), mildly to moderately malnourished (group B), and severely malnourished (group C). The number in each group was 275 (54.4%), 214 (42.4%), and 16 (3.2%), respectively. ANOVA tests revealed significant group differences existed for body mass index (BMI), triceps skinfold thickness (TSF), PA, ALB, length of stay, and in-hospital medical expenditures (p<0.05). The more severely malnourished the patient, the BMI, TSF, PA, and ALB became lower, the length of stay became longer and the medical cost became higher. The occurrence of postoperative complications did not show significant difference among the different SGA groups (X(2)=4.16, p=0.125). And patients in different cancer stages (TNM staging) had no statistical differences in terms of their length of stay (F=1.433, p=0.232) and the occurrence of postoperative complications (X(2)=4.836, p=0.184). CONCLUSIONS: The SGA is safe, inexpensive, and easy to use clinically for nurses. This study demonstrated that it can be a reliable method to assess the nutritional status of Chinese patients with gastrointestinal cancer. The SGA could also help predict certain health outcomes, such as length of stay, in-hospital medical expenditures.

Clinical application of subjective global assessment in Chinese patients with gastrointestinal cancer.

AIM: To investigate the role of subjective global assessment (SGA) in nutritional assessment and outcome prediction of Chinese patients with gastrointestinal cancer. METHODS: A total of 751 patients diagnosed with gastrointestinal cancer between August 2004 and August 2006 were enrolled in this study. Within 72 h after admission, SGA, anthropometric parameters, and laboratory tests were used to assess the nutritional status of each patient. The outcome variables including hospital stay, complications, and in-hospital medical expenditure were also obtained. RESULTS: Based on the results of SGA, 389 (51.8%), 332 (44.2%), and 30 (4.0%) patients were classified into well nourished group (SGA-A), mildly to moderately malnourished group (SGA-B), and severely malnourished group (SGA-C), respectively. The prevalence of malnutrition classified by SGA, triceps skinfold thickness (TSF), mid-upper arm muscle circumference (MAMC), albumin (ALB), prealbumin (PA), and body mass index (BMI) was 48.2%, 39.4%, 37.7%, 31.3%, 21.7%, and 9.6%, respectively. In addition, ANOVA tests revealed significant differences in body mass index (BMI), TSF, PA, and ALB of patients in different SGA groups. The more severely malnourished the patient was, the lower the levels of BMI, TSF, PA, and ALB were (P < 0.05). Chi2 tests showed a significant difference in SGA classification between patients receiving different types of treatment (surgery vs chemotherapy/radiotherapy). As the nutritional status classified by SGA deteriorated, the patients stayed longer in hospital and their medical expenditures increased significantly. Furthermore, multiple regression analysis showed that SGA and serum ALB could help predict the medical expenditures and hospital stay of patients undergoing surgery. The occurrence of complications increased in parallel with the increasing grade of SGA, and was the highest in the SGA-C group (23.3%) and the lowest in the SGA-A group (16.8%). CONCLUSION: SGA is a reliable assessment tool and helps to predict the hospital stay and medical expenditures of Chinese surgical gastrointestinal cancer patients.