Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival.

PURPOSE: Implantable intrathecal drug delivery systems (IDDSs) have been used to manage refractory cancer pain, but there are no randomized clinical trial (RCT) data comparing them with comprehensive medical management (CMM). PATIENTS AND METHODS: We enrolled 202 patients on an RCT of CMM versus IDDS plus CMM. Entry criteria included unrelieved pain (visual analog scale [VAS] pain scores >/= 5 on a 0 to 10 scale). Clinical success was defined as >/= 20% reduction in VAS scores, or equal scores with >/= 20% reduction in toxicity. The main outcome measure was pain control combined with change of toxicity, as measured by the National Cancer Institute Common Toxicity Criteria, 4 weeks after randomization. RESULTS: Sixty of 71 IDDS patients (84.5%) achieved clinical success compared with 51 of 72 CMM patients (70.8%, P =.05). IDDS patients more often achieved >/= 20% reduction in both pain VAS and toxicity (57.7% [41 of 71] v 37.5% [27 of 72], P =.02). The mean CMM VAS score fell from 7.81 to 4.76 (39% reduction); for the IDDS group, the scores fell from 7.57 to 3.67 (52% reduction, P =.055). The mean CMM toxicity scores fell from 6.36 to 5.27 (17% reduction); for the IDDS group, the toxicity scores fell from 7.22 to 3.59 (50% reduction, P =.004). The IDDS group had significant reductions in fatigue and depressed level of consciousness (P <.05). IDDS patients had improved survival, with 53.9% alive at 6 months compared with 37.2% of the CMM group (P =.06). CONCLUSION: IDDSs improved clinical success in pain control, reduced pain, significantly relieved common drug toxicities, and improved survival in patients with refractory cancer pain

ADP-Ribosylation Factor (ARF) Interaction Is Not Sufficient for Yeast GGA Protein Function or Localization

Golgi-localized γ-ear homology domain, ADP-ribosylation factor (ARF)-binding proteins (GGAs) facilitate distinct steps of post-Golgi traffic. Human and yeast GGA proteins are only ∼25% identical, but all GGA proteins have four similar domains based on function and sequence homology. GGA proteins are most conserved in the region that interacts with ARF proteins. To analyze the role of ARF in GGA protein localization and function, we performed mutational analyses of both human and yeast GGAs. To our surprise, yeast and human GGAs differ in their requirement for ARF interaction. We describe a point mutation in both yeast and mammalian GGA proteins that eliminates binding to ARFs. In mammalian cells, this mutation disrupts the localization of human GGA proteins. Yeast Gga function was studied using an assay for carboxypeptidase Y missorting and synthetic temperature-sensitive lethality between GGAs and VPS27. Based on these assays, we conclude that non-Arf-binding yeast Gga mutants can function normally in membrane trafficking. Using green fluorescent protein-tagged Gga1p, we show that Arf interaction is not required for Gga localization to the Golgi. Truncation analysis of Gga1p and Gga2p suggests that the N-terminal VHS domain and C-terminal hinge and ear domains play significant roles in yeast Gga protein localization and function. Together, our data suggest that yeast Gga proteins function to assemble a protein complex at the late Golgi to initiate proper sorting and transport of specific cargo. Whereas mammalian GGAs must interact with ARF to localize to and function at the Golgi, interaction between yeast Ggas and Arf plays a minor role in Gga localization and function

Costs of plasticity: responses to desiccation decrease post-metamorphic immune function in a pond-breeding amphibian

1.   Phenotypic plasticity may allow an organism to respond to temporally variable opportunities for growth and risks of mortality. However, life-history theory assumes that there are often trade-offs between the benefits afforded by plasticity in one trait and the consequences of that plasticity on other traits that affect fitness. In organisms with a complex life cycle, trade-offs may occur between larval and post-metamorphic traits. 2.   Many amphibians metamorphose in temporary ponds, and may accelerate larval development to avoid mortality when a pond desiccates. A younger age at metamorphosis often results in reduced body size, but may also facilitate a trade-off with physiological traits that are linked to fitness in the adult stage. 3.   We investigated a potential trade-off between desiccation-driven acceleration of development rate and immune system responsiveness in a species that breeds exclusively in temporary ponds. We exposed Rana sylvatica (wood frog) tadpoles to four possible desiccation regimes and then assayed the cell-mediated immune response to a standardized foreign antigen, phytohaemagglutinin (PHA), injected 3 weeks after metamorphosis. We also quantified total leucocyte numbers from haematological smears to obtain a secondary measure of individual immunological condition. 4.   Animals exposed to desiccation had shorter development times, weaker cellular immune system responses to PHA and lower total leucocyte numbers than animals from control groups. Both measures of immune response showed a decrease with increasing severity of the desiccation treatment. 5.   It is currently unclear whether the observed depression in immune response is transient or permanent. However, even temporary periods of immune system suppression shortly after metamorphosis may lead to greater susceptibility to opportunistic pathogens or parasites.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74472/1/j.1365-2435.2007.01340.x.pd