Publications

OBJECTIVE

To evaluate the efficacy, safety, and tolerability of oral SCIO-469, a p38 MAPK inhibitor that blocks tumor necrosis factor-α, interleukin-1ß, and cyclooxygenase-2 synthesis in patients with active rheumatoid arthritis (RA).

METHODS

Patients were randomized to receive SCIO-469 at either 30 or 60 mg three times daily in an immediate-release (IR) formulation or at 100 mg once daily in an extended-release (ER) formulation, or placebo for 24 weeks. The primary endpoint was American College of Rheumatology (ACR)20 response at Week 12. Safety was monitored through Week 26.

RESULTS

Overall, 302 patients were randomized: 76 to placebo, 75 to 30 mg IR, 73 to 60 mg IR, and 78 to 100 mg ER. There were no significant differences in ACR20 responses at Week 12 between SCIO-469 and placebo. Declines in C-reactive protein and erythrocyte sedimentation rate during early treatment did not persist to Week 12 and were not a consequence of decreased SCIO-469 plasma levels. The 60 mg IR regimen showed a dose-limiting toxicity manifested by elevations in alanine aminotransferase. Adverse events were common in all groups (79.7% and 86.7% through 13 and 26 weeks, respectively). Twenty-one patients reported 28 serious adverse events (SAE). SAE were more common with IR SCIO-469 than with placebo (7% vs 4%) but were not reported with ER SCIO-469.

CONCLUSION

In all regimens tested, SCIO-469 showed no greater efficacy compared to placebo in patients with RA. The transient effect of SCIO-469 on acute-phase reactants suggests a complex role of p38 MAPK in inflammation.

Histone deacetylases (HDACs) regulate the acetylation of a variety of histone and nonhistone proteins, controlling the transcription and regulation of genes involved in cell cycle control, proliferation, survival, DNA repair and differentiation. Unsurprisingly, HDAC expression is frequently altered in hematologic and solid tumor malignancies. Two HDAC inhibitors (vorinostat and romidepsin) have been approved by the US FDA for the treatment of cutaneous T-cell lymphoma. As single agents, treatment with HDAC inhibitors has demonstrated limited clinical benefit for patients with solid tumors, prompting the investigation of novel treatment combinations with other cancer therapeutics. In this article, the rationales and clinical progress of several combinations with HDAC inhibitors are presented, including DNA-damaging chemotherapeutic agents, radiotherapy, hormonal therapies, DNA methyltransferase inhibitors and various small-molecule inhibitors. The future application of HDAC inhibitors as a treatment for cancer is discussed, examining current hurdles to overcome before realizing the potential of this new approach.

OBJECTIVES

To evaluate how accounting for driving status altered the relationship between volunteering and mortality in U.S. retirees.

DESIGN

Observational prospective cohort.

SETTING

Nationally representative sample from the Health and Retirement Study in 2000 and 2002 followed to 2006.

PARTICIPANTS

Retirees aged 65 and older (N=6,408).

MEASUREMENTS

Participants self-reported their volunteering, driving status, age, sex, race or ethnicity, presence of chronic conditions, geriatric syndromes, socioeconomic factors, functional limitations, and psychosocial factors. Death by December 31, 2006, was the outcome.

RESULTS

For drivers, mortality in volunteers (9%) and nonvolunteers (12%) was similar; for limited or non-drivers, mortality for volunteers (15%) was markedly lower than for nonvolunteers (32%). Adjusted results showed that, for drivers, the volunteering-mortality odds ratio (OR) was 0.90 (95% confidence interval (CI)=0.66-1.22), whereas for limited or nondrivers, the OR was 0.62 (95% CI=0.49-0.78) (interaction P=.05). The effect of driving status was greater for rural participants, with greater differences between rural drivers and rural limited or nondrivers (interaction P=.02) and between urban drivers and urban limited or nondrivers (interaction P=.81).

CONCLUSION

The influence of volunteering in decreasing mortality seems to be stronger in rural retirees who are limited or nondrivers. This may be because rural or nondriving retirees are more likely to be socially isolated and thus receive more benefit from the greater social integration from volunteering.

Magnetic resonance (MR) imaging and histopathology were used to diagnose an articular process synovial myxoma in a dog. On MR images, the tumor was characterized by distortion of the left L1-L2 articular process, widening of the articular process joint, and the presence of a mass contiguous with the synovium of the articular process that displaced the spinal cord. The tumor was T2-hyperintense, T1-hypointense, relative to muscle, and had mild contrast enhancement. The MR features of articular process synovial myxoma may be distinct from other diseases of the articular process joint.