Correlating chemical sensitivity and basal gene expression reveals mechanism of action.

Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity across many cell lines to illuminate the actions of compounds whose MoA are unknown. To test this idea, we correlated the sensitivity patterns of 481 compounds with ∼19,000 basal transcript levels across 823 different human cancer cell lines and identified selective outlier transcripts. This process yielded many novel mechanistic insights, including the identification of activation mechanisms, cellular transporters and direct protein targets. We found that ML239, originally identified in a phenotypic screen for selective cytotoxicity in breast cancer stem-like cells, most likely acts through activation of fatty acid desaturase 2 (FADS2). These data and analytical tools are available to the research community through the Cancer Therapeutics Response Portal.

A systematic review of the association between depression and health care utilization in children and adults with sickle cell disease.

Patients with sickle cell disease (SCD) experience a disproportionately high use of health care resources. Several studies have examined depression and other negative mood states as risk factors for increased health care utilization; however, there have been no systematic reviews examining and summarizing this evidence in SCD. The aim of this systematic review, therefore, was to determine whether depression or depressive symptoms are associated with health care utilization among children and adults with SCD. We followed a quantitative systematic review protocol based on the Preferred Reporting Items for Systematic Reviews and Meta- Analyses guidelines and performed a literature search of records from January 1980 to April 2014 using six databases. Empirical studies were eligible if the sample was primarily composed of patients with SCD and included data on depression, mood disorder diagnosis or depressive symptoms and health care utilization. We included 12 studies involving 54 036 unique participants. The prevalence estimates for depression ranged from 2-57%. Seven studies found a significant, or marginally significant, association between depression and utilization while five did not. Patients reporting depression had an estimated 2·8 times greater relative risk of being a high utilizer, and 2·9 versus 1·8 hospitalizations per year on average compared to patients without depression. Overall, depressive symptoms are common in SCD and may increase risk for poor outcomes including health care utilization. The available studies on depression in SCD, however, are limited by small sample sizes, retrospective designs or short follow-up. This systematic review found a modest association between depression and health care utilization in SCD.

Influence of Spirituality on Depression-Induced Inflammation and Executive Functioning in a Community Sample of African Americans.

African Americans (AAs) are disproportionately affected by cerebrovascular pathology and more likely to suffer from premature cognitive decline. Depression is a risk factor for poorer cognitive functioning, and research is needed to identify factors that serve to mitigate its negative effects. Studies have demonstrated positive influences of spirituality within the AA community. Determining whether spirituality attenuates the effects of depressive symptoms on cognitive functioning and the pathophysiological mechanisms that explain these relationships in AAs is paramount. This study examines the influence of daily spiritual experiences on the relationship between depressive symptoms and cognitive functioning, and how inflammatory markers may partially explain these associations. A sample of 212 (mean age= 45.6) participants completed the Daily Spiritual Experience Scale (DSES), Beck Depression Inventory-II (BDI-II), Trail Making Test A and B (TMT) and Stroop Color and Word Test (Stroop). Blood samples were collected to measure inflammatory mediators (IL-6, IL-1a, TNF-a). Linear regression analyses were used to evaluate associations. Higher BDI-II scores were associated with poorer psychomotor speed and visual scanning, measured by TMT A (B=1.49, P=.01). IL-6 explained a significant amount of variance in this relationship (B=.24, CI 95% [.00, .64]). IL-6 also significantly mediated the relationship between depressive symptoms and psychomotor speed and mental flexibility, measured by TMT B performance (B=.03, CI 95% [.003, .095]). Frequent spiritual experiences among AAs may ameliorate the negative influence of depressive symptoms on cognitive functioning.

1-Tetradecanol complex reduces progression of Porphyromonas gingivalis-induced experimental periodontitis in rabbits.

BACKGROUND: It has been recently shown that monounsaturated fatty acids inhibit endothelial activation and reduce tissue responsiveness to cytokines. The present study has been planned to investigate topical application of a novel monounsaturated fatty acid complex (1-tetradecanol complex) for prevention of Porphyromonas gingivalis-induced periodontitis in rabbits. METHODS: Experimental periodontitis was induced in New Zealand white rabbits with silk sutures tied around the mandibular second premolars bilaterally, followed by the topical application of 10(9) colony forming units (CFU) of P. gingivalis. 1-Tetradecanol complex (1-TDC) was topically applied at 1- and 10-mg/ml concentrations in five animals in each group, whereas control animals received olive oil vehicle (five animals) three times per week for 6 weeks. Negative controls included ligature alone (14 animals) or ligature + P. gingivalis (non-treatment; 15 animals). Rabbits were sacrificed after 6 weeks, and mandibular block sections were obtained; tissues were decalcified and embedded in paraffin. Thin sections (5 microm) were stained with hematoxylin and eosin or tartrate-resistant acid phosphatase. Macroscopic and histologic evaluation of samples was followed by the characterization of cellular inflammatory infiltrate and quantitative histomorphometric measurements. RESULTS: Treatment with both concentrations of 1-TDC and vehicle resulted in significant prevention of macroscopic periodontal inflammation and bone loss (75%; P <0.05) compared to the non-treatment (ligature + P. gingivalis) group, where significant periodontal tissue destruction characterized by attachment and bone loss was detected. However, there was no statistically significant difference between the vehicle and both 1-TDC groups. Histologically, 1-TDC inhibited inflammatory cell infiltration and prevented osteoclastogenesis, whereas treatment with vehicle did not show the same effect as in the 1-TDC groups; the difference between vehicle and the higher concentration of 1-TDC (10 mg/ml) was statistically significant. CONCLUSION: Topical application of an esterified monounsaturated fatty acid complex (1-TDC) was found promising in preventing bone loss, inflammatory cell infiltration, and connective tissue destruction in the rabbit periodontitis model.