Apoptosis has been accepted as a fundamental component in the pathogenesis of cancer, in addition to other human diseases including neurodegeneration, coronary disease and diabetes. The origin of cancer involves deregulated cellular proliferation and the suppression of apoptotic processes, ultimately leading to tumor establishment and growth. Several lines of evidence point toward the IAP family of proteins playing a role in oncogenesis, via their effective suppression of apoptosis. The central mechanisms of IAP apoptotic suppression appear to be through direct caspase and pro-caspase inhibition (primarily caspase 3 and 7) and modulation of, and by, the transcription factor NF-kappaB. Thus, when the IAPs are over-expressed or over-active, as is the case in many cancers, cells are no longer able to die in a physiologically programmed fashion and become increasingly resistant to standard chemo- and radiation therapies. To date several approaches have been taken to target and eliminate IAP function in an attempt to re-establish sensitivity, reduce toxicity, and improve efficacy of cancer treatment. In this review, we address IAP proteins as therapeutic targets for the treatment of cancer and emphasize the importance of novel therapeutic approaches for cancer therapy. Novel targets of IAP function are being identified and include gene therapy strategies and small molecule inhibitors that are based on endogenous IAP antagonists. As well, molecular mechanistic approaches, such as RNAi to deplete IAP expression, are in development.

Cytotoxic lymphocytes employ Granzyme B as a potent initiator of apoptosis to cleave and activate effector caspases. Unexpectedly, cells transfected with Bcl-2 were resistant to granzyme B-induced killing, suggesting that a mitochondrial pathway was critical. Utilizing cells expressing a dominant-negative caspase 9, the current study demonstrated that caspase activation via the apoptosome was not required. Indeed, cleavage of caspase 3 to p20 still occurred in Bcl-2-transfectants but processing to p17 was blocked. This blockade was recapitulated by the Inhibitor-of-Apoptosis-Protein XIAP and relieved by Smac/DIABLO. Thus granzyme B mediates direct cleavage of caspase 3 and also activates mitochondrial disruption, resulting in the release of proapoptotic proteins that suppress caspase inhibition. Engagement of both pathways is critical for granzyme-induced killing.

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Smac/DIABLO is a mitochondrial protein that is proteolytically processed and released during apoptosis along with cytochrome c and other proapoptotic factors. Once in the cytosol, Smac protein binds to inhibitors of apoptosis (IAP) proteins and disrupts the ability of the IAPs to inhibit caspases 3, 7, and 9. The requirement for mitochondrial processing and release has complicated efforts to delineate the effect of Smac overexpression and IAP inhibition on cell death processes. In this report, we document a novel expression system using ubiquitin fusions to express mature, biologically active

IntroductionIn January 2012 an acute care surgery (ACS) model was introduced at St. Paul’s Hospital, Saskatoon, Saskatchewan. The goal of implementing an ACS service was to improve the delivery of care for emergent, non-trauma surgical patients. We examined whether the ACS model improved wait time to surgery, decreased the proportion of surgeries performed after hours, and shortened post-surgical length of stay. We also assessed whether the surgeons working in an ACS system had higher on-call satisfaction than surgeons working in a non- ACS system.MethodsA retrospective pre-post analysis was performed using data from the Discharge Abstract Database and the Organizing Medical Networked Information database. Surgeon satisfaction was evaluated using a questionnaire that was mailed to all general surgeons in Saskatoon.ResultsAn ACS service significantly reduced wait time to surgery for patients with all acute general surgery diagnoses from 221 minutes to 192 minutes (ρ = 0.015; CI = 5.8-52.2). Post-surgery length of stay for patients operated on for acute appendicitis, or acute cholecystitis was not reduced. On average, patients with bowel obstruction had increased length of stay following ACS service implementation. Most surgeries in our study were performed between 16:00 hours and 08:00 hours but the introduction of an ACS significantly reduced the number of afterhours surgeries (60.0% vs. 72.6%) (ρ < 0.0001). Our survey had a response rate of 75%. Overall, surgeons on an ACS service had greater satisfaction with the organization of their call schedule than surgeons not on an ACS service.ConclusionIntroduction of an ACS service in Saskatoon has decreased wait time to surgery and reduced the proportion of afterhours emergency surgeries, with no reduction in the length of post-surgery hospital stay. Satisfaction may be higher for surgeons in an ACS service.

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