Survival duration among patients with a noncancer diagnosis admitted to a palliative care unit: a retrospective study.

BACKGROUND: Palliative care unit (PCU) beds are a limited resource in Canada, so PCU admission is restricted to patients with a short prognosis. Anecdotally, PCUs further restrict admission of patients with noncancer diagnoses out of fear that they will "oversurvive" and reduce bed availability. This raises concerns that noncancer patients have unequal access to PCU resources. PURPOSE/METHODS: To clarify survival duration of patients with a noncancer diagnosis, we conducted a retrospective review of all admissions to four PCUs in Toronto, Canada, over a 1-year period. We measured associations between demographic data, prognosis, Palliative Performance Score (PPS), length of stay (LOS), and waiting time. RESULTS: We collected data for 1000 patients, of whom 21% had noncancer diagnoses. Noncancer patients were older, with shorter prognoses and lower PPS scores on admission. Noncancer patients had shorter LOS (14 versus 24, p<0.001) than cancer patients and a similar likelihood of being discharged alive to cancer patients. Noncancer patients had a trend to lower LOS across a broad range of demographic, diagnostic, prognostic, and PPS categories. Multivariable analysis showed that LOS was not associated with the diagnosis of cancer (p=0.36). DISCUSSION/CONCLUSION: Noncancer patients have a shorter LOS than cancer patients and a similar likelihood of being discharged alive from a PCU than cancer patients, and the diagnosis of cancer did not correlate with survival in our study population. Our findings demonstrate that noncancer patients are not "oversurviving," and that referring physicians and PCUs should not reject or restrict noncancer referrals out of concern that these patients are having a detrimental impact on PCU bed availability.

An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme.

In the ubiquitin-proteasome system (UPS), E2 enzymes mediate the conjugation of ubiquitin to substrates and thereby control protein stability and interactions. The E2 enzyme hCdc34 catalyzes the ubiquitination of hundreds of proteins in conjunction with the cullin-RING (CRL) superfamily of E3 enzymes. We identified a small molecule termed CC0651 that selectively inhibits hCdc34. Structure determination revealed that CC0651 inserts into a cryptic binding pocket on hCdc34 distant from the catalytic site, causing subtle but wholesale displacement of E2 secondary structural elements. CC0651 analogs inhibited proliferation of human cancer cell lines and caused accumulation of the SCF(Skp2) substrate p27(Kip1). CC0651 does not affect hCdc34 interactions with E1 or E3 enzymes or the formation of the ubiquitin thioester but instead interferes with the discharge of ubiquitin to acceptor lysine residues. E2 enzymes are thus susceptible to noncatalytic site inhibition and may represent a viable class of drug target in the UPS.

Dcn1 functions as a scaffold-type E3 ligase for cullin neddylation.

Cullin-based E3 ubiquitin ligases are activated through modification of the cullin subunit with the ubiquitin-like protein Nedd8. Dcn1 regulates cullin neddylation and thus ubiquitin ligase activity. Here we describe the 1.9 A X-ray crystal structure of yeast Dcn1 encompassing an N-terminal ubiquitin-binding (UBA) domain and a C-terminal domain of unique architecture, which we termed PONY domain. A conserved surface on Dcn1 is required for direct binding to cullins and for neddylation. The reciprocal binding site for Dcn1 on Cdc53 is located approximately 18 A from the site of neddylation. Dcn1 does not require cysteine residues for catalytic function, and directly interacts with the Nedd8 E2 Ubc12 on a surface that overlaps with the E1-binding site. We show that Dcn1 is necessary and sufficient for cullin neddylation in a purified recombinant system. Taken together, these data demonstrate that Dcn1 is a scaffold-like E3 ligase for cullin neddylation.

Inhibition of lymphotoxin-beta receptor-mediated cell death by survivin-DeltaEx3.

TNFSF14/LIGHT is a member of the tumor necrosis factor superfamily that binds to lymphotoxin-beta receptor (LTbetaR) to induce cell death via caspase-dependent and caspase-independent pathways. It has been shown that cellular inhibitor of apoptosis protein-1 inhibits cell death by binding to LTbetaR-TRAF2/TRAF3 complexes and caspases. In this study, we found that both Kaposi's sarcoma-associated herpesvirus K7 (KSHV-K7), a viral inhibitor of apoptosis protein, and the structurally related protein survivin-DeltaEx3 could inhibit LTbetaR-mediated caspase-3 activation. However, only survivin-DeltaEx3 could protect cells from LTbetaR-mediated cell death. The differential protective effects of survivin-DeltaEx3 and KSHV-K7 can be attributed to the fact that survivin-DeltaEx3, but not KSHV-K7, is able to maintain mitochondrial membrane potential and inhibit second mitochondria-derived activator of caspase/DIABLO release. Moreover, survivin-DeltaEx3 is able to inhibit production of reactive oxygen species and can translocate from nucleus to cytosol to associate with apoptosis signal-regulating kinase 1 after activation of LTbetaR. Furthermore, survivin-DeltaEx3 protects LTbetaR-mediated cell death in caspase-3-deficient MCF-7 cells. Thus, survivin-DeltaEx3 is able to regulate both caspase-dependent and caspase-independent pathways, whereas inhibition of caspase-independent pathway is both sufficient and necessary for its protective effect on LTbetaR-mediated cell death.

Proinflammatory effects of LIGHT through HVEM and LTbetaR interactions in cultured human umbilical vein endothelial cells.

Members of the tumor necrosis factor (TNF) receptor (TNFR) superfamily are known to be potent mediators of immune responses. LIGHT is a member of the TNF superfamily, and its receptors have been identified as lymphotoxin beta receptor (LTbetaR), herpes virus entry mediator (HVEM), and decoy receptor 3 (DcR3). LIGHT can induce either cell death and/or NF-kappaB activation via its interaction with LTbetaR and/or HVEM. In this study, we investigated the effects of LIGHT in human umbilical vein endothelial cells (HUVECs). We demonstrated that both LTbetaR and HVEM, but not DcR3, are present in HUVECs, and LIGHT can induce the secretion of chemokines (IL-8 and GRO-alpha), cell surface expression of adhesion molecules (ICAM-1 and VCAM-1), PGI2 release, and COX-2 expression. However, the LIGHT mutein, LIGHT-R228E, which has been shown to exhibit binding specificity to LTbetaR, could not induce the secretion of GRO-alpha, PGI2, or the expression of COX-2. These results indicate that both LTbetaR and HVEM can discriminatively mediate the expression of different genes in HUVECs, and suggest that LIGHT is a proinflammatory cytokine.

The role of apoptosis signal-regulating kinase 1 in lymphotoxin-beta receptor-mediated cell death.

LIGHT (homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes) is a member of the tumor necrosis factor superfamily that can interact with lymphotoxin-beta receptor (LTbetaR), herpes virus entry mediator, and decoy receptor (DcR3). In our previous study, we showed that LIGHT is able to induce cell death via the non-death domain containing receptor LTbetaR to activate both caspase-dependent and caspase-independent pathway. In this study, a LIGHT mutein, LIGHT-R228E, was shown to exhibit similar binding specificity as wild type LIGHT to LTbetaR, but lose the ability to interact with herpes virus entry mediator. By using both LIGHT-R228E and agonistic anti-LTbetaR monoclonal antibody, we found that signaling triggered by LTbetaR alone is sufficient to activate both caspase-dependent and caspase-independent pathways. Cross-linking of LTbetaR is able to recruit TRAF3 and TRAF5 to activate ASK1, whereas its activity is inhibited by free radical scavenger carboxyfullerenes. The activation of ASK1 is independent of caspase-3 activation, and kinase-inactive ASK1-KE mutant can inhibit LTbetaR-mediated cell death. This suggests that ASK1 is one of the factors involved in the caspase-independent pathway of LTbetaR-induced cell death.