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Multidrug resistance is a serious barrier to successful treatment of many human diseases, including cancer, wherein chemotherapeutics are exported from target cells by membrane-embedded pumps. The most prevalent of these pumps, the ATP-Binding Cassette transporter P-glycoprotein (P-gp), consists of two homologous halves each comprising one nucleotide-binding domain and six transmembrane helices. The transmembrane region encapsulates a hydrophobic cavity, accessed by portals in the membrane, that binds cytotoxic compounds as well as lipids and peptides. Here we use mass spectrometry (MS) to probe the intact P-gp small molecule-bound complex in a detergent micelle. Activation in the gas phase leads to formation of ions, largely devoid of detergent, yet retaining drug molecules as well as charged or zwitterionic lipids. Measuring the rates of lipid binding and calculating apparent KD values shows that up to six negatively charged diacylglycerides bind more favorably than zwitterionic lipids. Similar experiments confirm binding of cardiolipins and show that prior binding of the immunosuppressant and antifungal antibiotic cyclosporin A enhances subsequent binding of cardiolipin. Ion mobility MS reveals that P-gp exists in an equilibrium between different states, readily interconverted by ligand binding. Overall these MS results show how concerted small molecule binding leads to synergistic effects on binding affinities and conformations of a multidrug efflux pump.

Tobacco use among young adults is a major public health challenge. Near-term benefits of cessation may motivate active young people to quit or avoid smoking. Military basic training includes mandatory tobacco cessation, as well as uniform physical conditioning regimes, creating an opportunity to evaluate changes in physical performance metrics in direct relation to smoking cessation. These analyses included data from all men who completed Marine Corps recruit training in San Diego, California, between 2002 and 2006. Recruits reported tobacco use and other health metrics on a pretraining survey. Initial and final aerobic run-times were recorded over the 3-month training period. Multivariable linear regression analyses assessed changes in run-speed relative to pre-enlistment smoking history. Among 52,419 young men included in analyses, 13,248 (25.3%) reported smoking before enlistment. Average run-speeds improved among all groups of recruits; however, improvement was greater among prior smokers compared to recruits with no history of smoking (average increase of 0.31 vs. 0.21 miles per hour) and statistically significant in multivariate analyses. Smoking cessation in this cohort of young men resulted in improved physical aerobic performance, independent of other behavioral health characteristics. These data may be useful in promoting and motivating smoking cessation among young, active adults.

In a large randomized trial involving over 2,000 women with abnormal cervical cytology (pap smear), three clinic-based interventions were tested as strategies to increase return rates for screening follow-up: 1) a personalized follow-up letter and pamphlet; 2) a slide-tape program on pap smears; and 3) transportation incentives (bus passes/parking permits). The three interventions were evaluated using a 2 × 2 × 2 factorial design. Results of this study confirm a high rate of loss to screening follow-up (i.e., no return visits) among women with abnormal pap smears (29% overall), with substantial variability among the 12 participating clinics (13% to 42/%). For the sample as a whole, both transportation incentives and the combined intervention condition of personalized follow-up and slide-tape program had a significant positive impact on screening follow-up. However, transportation incentives emerged as the dominant intervention condition among patient subgroups that can be characterized as more disadvantaged socioeconomically and at higher risk of developing cervical cancer, including patients receiving care from the county health department (odds ratio (OR) = 1.51; P<.05); patients without health insurance (OR = 1.77; P<.01); and patients with more severe pap smear results (OR = 1.71; P<.05). In contrast, among patient subgroup that can be characterized as relatively more advantaged and at lower risk of developing cervical cancer, only the combined intervention condition of personalized follow-up and slide-tape program was associated with a higher patient return rate. Subgroups reflecting this pattern included patients seen in noncounty clinics (OR = 4.54; P<.05) and patients with less severe pap smear results (OR = 5.16; P<.01). The implications of these findings are discussed in terms of designing clinic-based interventions to improve screening follow-up.