It rises from above that signaling pathways that lead to the truly expression and the stability of Bim will actively con tribute to render Mcl 1 expression required for survival. Our finding that Bim expression can be detected in lysates that were prepared from 5 HER2 amplified tumors that had received no treatment indicate that such pathways are active in this malignancy. Mechan isms that regulate Inhibitors,Modulators,Libraries Bim transcription in particular might be effective, as suggested by the possible enrichment for some Bim transcripts in HER2 amplified tumors revealed by our investigation of publicly available expression data from breast cancer. Our finding that RAD001 negatively regulates Bim expression indicate that mTORC1, which plays an important oncogenic role in HER2 amplified tumors, might contribute to this expression.

The pro apoptotic role our data attribute to the mTOR pathway is somewhat reminiscent to that reported for its downstream kinase S6K in hepatocytes, where S6K contributes to Bim expression. Our data suggest that mTORC1 favors Bim expression by control ling the expression and the activity of c Myc, and that this transcription factor is involved Inhibitors,Modulators,Libraries is the constitutive expression of Bim in BT474 cells. The results of our ChIP assays indicate that RAD001 sensitive c Myc might be directly involved in the transcription of Bim in BT474 cells. As the mTOR pathway is frequently active in HER2 overexpressing breast cancers and regulates c Myc activity, our results imply that the corresponding tumor cells might frequently express constitutive Bim.

This constitute a molecular vulnerability that renders the sustained anti apoptotic activity of Mcl 1 necessary for survival. Thus, one promising approach for the treat ment of HER2 overexpressing breast cancers might be one that relies on the use of inhibitors of the anti apoptotic Inhibitors,Modulators,Libraries activity of Mcl 1. Conclusions Inhibitors,Modulators,Libraries Our work provides strong support to the notion that some tumor cells might depend upon a limited number of anti apoptotic Bcl 2 like proteins for their survival. It establishes that this Bcl 2L dependence Inhibitors,Modulators,Libraries extends to HER2 amplified tumors, and that, in these tumors, it relies, at least in part, references on the interconnected pathways that lead to pro apoptotic Bim and anti apop totic Mcl 1 expressions. This implies that current tar geted approaches need to influence the balance between Bim and Mcl 1 to efficiently affect cancer cell survival. It also implies that novel strategies that directly act upon this balance without interfering with the rest of the HER2 network are a promising alternative for the treatment of this disease.

32% agreed or strongly agreed that they had changed their nutrition practice as a result of study participation. On average nurses were exposed to 7 study related activities or resources, and on average rated these as 4 somewhat useful. Table 4 describes Inhibitors,Modulators,Libraries the results of the evaluation questionnaire by site. A total of 182 critical care staff nurses, 25 physicians,12 dietitians and 11 other responded to the Barriers to Enterally Feeding Critically Ill Patients questionnaire at baseline, and 118 nurses, 12 physicians, 10 dietitians and 3 other at follow up. for an overall response rate of 45% and 29% at the two respective time points. Respondent characteristics were similar at baseline and follow up. Over half were experienced staff working in ICU for greater than five years, and two thirds worked full time.

Figure 2 illustrates the change in prioritized barriers score reflecting barriers Inhibitors,Modulators,Libraries targeted for improvement by the tailored action plans at each site. The prioritized barriers score Inhibitors,Modulators,Libraries decreased in all sites between baseline and follow up with a mean change of 13 points ranging from 5 at Site 1 to 26 at Site 4. We observed a 10 point reduction in overall Inhibitors,Modulators,Libraries barriers score. The barriers score decreased for all 21 items in the questionnaire and this change was statistically significant for 16 items. The greatest change was observed in subscales 4 and 5 with a change in barriers score of 12 points and 11 points. Although the barriers score decreased at all sites for most items, the magnitude of change varied. There were 140 patients accrued in the nutrition practice audit at baseline and 138 at follow up.

Patient characteristics and clinical outcomes were similar at both time points, 55% were male with a median age of 61 years, and BMI of 27Kg m2. The majority were medical patients and the median APACHE II score was 22. The median energy and protein prescribed by the dietitian was 1745 Kcals and 96 grams respectively. In 79% of patients these energy requirements were calculated Inhibitors,Modulators,Libraries using a weight based formula ranging from 20 30 Kcals per Kg. The protein prescriptions were also calculated using a weight based formula. Median lengths of mechanical ventilation and ICU stay were 5 days and 8 days respectively, and 60 day hospital mortality was 25. 5%. Figure 3a shows the change in caloric adequacy from total nutrition at each site.

While some sites did not improve, an increase of 10% was observed at two sites. Similar results were observed for protein adequacy from total all targets nutrition. Discussion In this multicenter study of a tailored intervention to improve the provision of EN to critically ill patients, we demonstrated that this multi faceted, interdisciplinary intervention is feasible with all 5 sites successfully developing and implementing their action plans.