Introduction A subpopulation (CD44 + /CD24 -) of breast cancer cells has been reported to have stem/progenitor cell properties. The aim of this study was to investigate whether this subpopulation of cancer cells has the unique ability to invade, home, and proliferate at sites of metastasis.

Parthenolide, a sesquiterpene lactone, shows antitumor activity in vitro, which correlates with its ability to inhibit the DNA binding of the antiapoptotic transcription factor nuclear factor KB (NF-KB) and activation of the c-Jun NH 2 -terminal kinase. In this study, we investigated the chemosensitizing activity of parthenolide in vitro as well as in MDA-MB-231 cell -derived xenograft metastasis model of breast cancer. HBL-100 and MDA-MB-231 cells were used to measure the antitumor and chemosensitizing activity of parthenolide in vitro. Parthenolide was effective either alone or in combination with docetaxel in reducing colony formation, inducing apoptosis and reducing the expression of prometastatic genes IL-8 and the antiapoptotic gene GADD45b1 in vitro. In an adjuvant setting, animals treated with parthenolide and docetaxel combination showed significantly enhanced survival compared with untreated animals or animals treated with either drug. The enhanced survival in the combination arm was associated with reduced lung metastases. In addition, nuclear NF-KB levels were lower in residual tumors and lung metastasis of animals treated with parthenolide, docetaxel, or both. In the established orthotopic model, there was a trend toward slower growth in the parthenolide-treated animals but no statistically significant findings were seen. These results for the first time reveal the significant in vivo chemosensitizing properties of parthenolide in the metastatic breast cancer setting and support the contention that metastases are very reliant on activation of NF-KB. [Mol Cancer Ther 2005;4(6):1004 -12]

Serum HGF is elevated in obese individuals. This study examined the contribution of excess adipose tissue to increased circulating HGF levels in obesity. Serum HGF was measured by ELISA before and after weight loss due to bariatric surgery or a 24-h fast. At 6.1 ± 0.1 mo following surgery, BMI (50.6 ± 1.6 vs. 35.1 ± 1.3 kg/m2; P < 0.0001) and serum HGF were significantly decreased (1,164 ± 116 vs. 529 ± 39 pg/ml, P < 0.001). A 24-h fast did not change serum HGF, but serum leptin was significantly reduced (67.7 ± 7.1 vs. 50.3 ± 8.3 ng/ml, P = 0.02). HGF secretion in vitro from adipocytes of obese (BMI 40.3 ± 2.8 kg/m2) subjects was significantly greater (80.9 ± 10.4 vs. 21.5 ± 4.0 pg/105 cells, P = 0.008) than release from adipocytes of lean (BMI 23.3 ± 1.4 kg/m2) subjects. HGF mRNA levels determined by real-time RT-PCR were not different in adipocytes from lean (BMI 24.0 ± 0.8 kg/m2) and obese (45.7 ± 3.0 kg/m2) subjects, but serum HGF was significantly elevated in the obese individuals studied (787 ± 61 vs. 489 ± 49 pg/ml, P = 0.001). TNF-α (24 h treatment) significantly increased HGF release from subcutaneous adipocytes 23.6 ± 8.3% over control ( P = 0.02). These data suggest that elevated serum HGF in obesity is in part attributable to excess adipose tissue and that this effect can be reversed by reducing adipose tissue mass through weight loss. Increased HGF secretion from adipocytes of obese subjects may be due to posttranscriptional events possibly related to adipocyte size and stimulation by elevated TNF-α in the adipose tissue of obese individuals.

In humans, emotions from music serve important communicative roles. Despite a growing interest in the neural basis of music perception, action and emotion, the majority of previous studies in this area have focused on the auditory aspects of music performances. Here we investigate how the brain processes the emotions elicited by audiovisual music performances. We used event-related functional magnetic resonance imaging, and in Experiment 1 we defined the areas responding to audiovisual (musician's movements with music), visual (musician's movements only), and auditory emotional (music only) displays. Subsequently a region of interest analysis was performed to examine if any of the areas detected in Experiment 1 showed greater activation for emotionally mismatching performances (combining the musician's movements with mismatching emotional sound) than for emotionally matching music performances (combining the musician's movements with matching emotional sound) as presented in Experiment 2 to the same participants. The insula and the left thalamus were found to respond consistently to visual, auditory and audiovisual emotional information and to have increased activation for emotionally mismatching displays in comparison with emotionally matching displays. In contrast, the right thalamus was found to respond to audiovisual emotional displays and to have similar activation for emotionally matching and mismatching displays. These results suggest that the insula and left thalamus have an active role in detecting emotional correspondence between auditory and visual information during music performances, whereas the right thalamus has a different role.

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