In the present study, we tested the anti-pancreatic cancer activity by AT406, a small-molecule antagonist of IAP (inhibitor of apoptosis proteins). In established (Panc-1 and Mia-PaCa-2 lines) and primary human pancreatic cancer cells, treatment of AT406 significantly inhibited cell survival and proliferation. Yet, same AT406 treatment was non-cytotoxic to pancreatic epithelial HPDE6c7 cells. AT406 increased caspase-3/-9 activity and provoked apoptosis in the pancreatic cancer cells. Reversely, AT406′ cytotoxicity in these cells was largely attenuated with pre-treatment of caspase inhibitors. AT406 treatment caused degradation of IAP family proteins (cIAP1 and XIAP) and release of cytochrome C, leaving Bcl-2 unaffected in pancreatic cancer cells. Bcl-2 inhibition (by ABT-737) or shRNA knockdown dramatically sensitized Panc-1 cells to AT406. In vivo, oral administration of AT406 at well-tolerated doses downregulated IAPs (cIAP1/XIAP) and inhibited Panc-1 xenograft tumor growth in severe combined immunodeficient (SCID) nude mice. Together, our preclinical results suggest that AT406 could be further evaluated as a promising anti-pancreatic cancer agent.

The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse iv t(1/2) = 0.3 h, po F= 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (iv t(1/2) = 5.0 h, po F = 51%) but resulted in > 500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity. (c) 2006 Elsevier Ltd. All rights reserved.

Interstitial concentration of amyloid beta (Aß) is positively related to synaptic activity in animal experiments. In humans, Aß deposition in Alzheimer's disease overlaps with cortical regions highly active earlier in life. White matter lesions (WML) disrupt connections between gray matter (GM) regions which in turn changes their activation patterns. Here, we tested if WML are related to Aß accumulation (measured with PiB-PET) and glucose uptake (measured with FDG-PET) in connected GM. WML masks from 72 cognitively normal (age 61.7 ± 9.6 years, 71% women) individuals were obtained from T2-FLAIR. MRI and PET images were normalized into common space, segmented and parcellated into gray matter (GM) regions. The effects of WML on connected GM regions were assessed using the Change in Connectivity (ChaCo) score. Defined for each GM region, ChaCo is the percentage of WM tracts connecting to that region that pass through the WML mask. The regional relationship between ChaCo, glucose uptake and Aß was explored via linear regression. Subcortical regions of the bilateral caudate, putamen, calcarine, insula, thalamus and anterior cingulum had WM connections with the most lesions, followed by frontal, occipital, temporal, parietal and cerebellar regions. Regional analysis revealed that GM with more lesions in connecting WM and thus impaired connectivity had lower FDG-PET (r = 0.20, p < 0.05 corrected) and lower PiB uptake (r = 0.28, p < 0.05 corrected). Regional regression also revealed that both ChaCo (β = 0.045) and FDG-PET (β = 0.089) were significant predictors of PiB. In conclusion, brain regions with more lesions in connecting WM had lower glucose metabolism and lower Aß deposition.

Purpose: This study was initiated to compare the effectiveness of a traditional cardiac rehabilitation protocol (TP) to a lower cost modified cardiac rehabilitation protocol (MP) designed to promote off-site exercise adherence. Methods: Effectiveness was based on supervised and independent exercise adherence and selected physiological outcomes. Fifty one moderate and low risk patients (41 men, 10 women) completed maximal graded metabolic exercise tests upon entry and at three months. Rehabilitation based and off-site exercise adherence was documented weekly over three months. The first month, all subjects followed identical protocols; three ECG monitored exercise sessions per week with encouragement to exercise off-site to achieve≥ 5 times per week for ≥ 30 minutes a session. In the third week, patients were randomized to either the TP (n=25) or the MP (n=26). The TP involved three continuous ECG monitored exercise sessions per week for 12 weeks. The MP included the following: in week five ECG monitoring was discontinued, in week six, patients were weaned to two on-site exercise sessions per week and asked to attend a weekly education/ discussion group. In week 11, patients were weaned to one on-site exercise session per week.Results: The three month evaluation revealed the TP average billing cost per patient of $1,961 was $784 more than the MP ($1,177). This was primarily due to additional on-site ECG monitoring. The MP completed 16.5% less on-site exercise sessions (MP -22, TP- 26) however, overall they completed 12.5% more exercise due to more off-site sessions (MP- 37, TP- 27). Both protocols elicited significant increases in anaerobic threshold and peak VO2, and decreases in body mass index (P<.05), while the MP also showed greater reductions in submaximal RPP (p<.05). Conclusion: A well designed low cost program for cardiac rehabilitation can facilitate improved offsite exercise adherence and equal or superior physiological outcomes compared to a traditional protocol.