Cancer screening behaviors among smokers and non-smokers

Objective: We explored whether smoking is associated with cancer screening behaviors. Methods: We used data from the 2007 Florida Behavioral Risk Factor Surveillance System and the Florida Tobacco Callback Survey to examine screening behaviors related to four cancer types (breast, cervical, prostate, and colorectal). Using multiple logistic regression analyses, we examined the association between smoking status and health screening behaviors. Results: For 10 of the 11 cancer screening variables, being a current smoker was significantly associated with being less likely to ever have been screened and also less likely to be compliant with screening guidelines. For breast and cervical cancer, level of nicotine dependence was also significantly related to compliance with screening recommendations; women with higher levels of dependence were less likely to be compliant. Conclusions: Our results support the notion that individuals’ actions related to their health are consistent across different types of behaviors. We found that smokers were less likely to engage in cancer screening behaviors. In addition, among smokers, individuals with greater nicotine dependence had lower compliance with some screening tests. Physicians should ensure that their patients who smoke are receiving appropriate and adequate screening for cancer.     

Rab38 and Rab32 control post-Golgi trafficking of melanogenic enzymes

A mutation in the small GTPase Rab38 gives rise to the mouse coat color phenotype "chocolate" (cht), implicating Rab38 in the regulation of melanogenesis. However, its role remains poorly characterized. We report that cht Rab38(G19V) is inactive and that the nearly normal pigmentation in cht melanocytes results from functional compensation by the closely related Rab32. In cht cells treated with Rab32-specific small interfering RNA, a dramatic loss of pigmentation is observed. In addition to mature melanosomes, Rab38 and Rab32 localize to perinuclear vesicles carrying tyrosinase and tyrosinase-related protein 1, consistent with a role in the intracellular sorting of these proteins. In Rab38/Rab32-deficient cells, tyrosinase appears to be mistargeted and degraded after exit from the trans-Golgi network (TGN). This suggests that Rab38 and Rab32 regulate a critical step in the trafficking of melanogenic enzymes, in particular, tyrosinase, from the TGN to melanosomes. This work identifies a key role for the Rab38/Rab32 subfamily of Rab proteins in the biogenesis of melanosomes and potentially other lysosome-related organelles.     

Glial regulation of the axonal membrane at nodes of Ranvier

Action potential conduction in myelinated nerve fibers depends on a polarized axonal membrane. Voltage-gated Na(+) and K(+) channels are clustered at nodes of Ranvier and mediate the transmembrane currents necessary for rapid saltatory conduction. Paranodal junctions flank nodes and function as attachment sites for myelin and as paracellular and membrane protein diffusion barriers. Common molecular mechanisms, directed by myelinating glia, are used to establish these axonal membrane domains. Initially, heterophilic interactions between glial and axonal cell adhesion molecules define the locations where nodes or paranodes form. Subsequently, within each domain, axonal cell adhesion molecules are stabilized and retained through interactions with cytoskeletal and scaffolding proteins, including ankyrins and spectrins.     

Cyclopentane-based human NK1 antagonists. Part 1: discovery and initial SAR

An initial investigation of the novel cyclopentane scaffold 6 afforded low nanomolar human NK1 antagonists having enhanced water solubility properties compared to morpholine 1. A synthesis of this cyclopentane scaffold, having three contiguous chiral centers, and the unexpected determination that the 1,2-trans-2,3-trans-ring stereochemistry, as opposed to the cis-ether/phenyl configuration of the known structures 1-5, is optimal for this class of antagonist are described.     

Behavioural and hormonal responses to predation in female chacma baboons (Papio hamadryas ursinus)

In humans, bereavement is associated with an increase in glucocorticoid (GC) levels, though this increase can be mitigated by social support. We examined faecal GC levels and grooming behaviour of free-ranging female baboons to determine whether similar effects were also evident in a non-human species. Females who lost a close relative experienced a significant increase in GC levels in the weeks following their relative's death compared with the weeks before, whereas control females showed no such increase. Despite the fact that females concentrate much of their grooming on close kin, females who lost a close female relative did not experience a decrease in grooming rate and number of grooming partners; instead, both grooming rate and number of grooming partners increased after a relative's death. While the death of a close relative was clearly stressful over the short term, females appeared to compensate for this loss by broadening and strengthening their grooming networks. Perhaps as a result, females' GC levels soon returned to baseline. Even in the presence of familiar troop-mates and other relatives, females experienced a stress response when they lost specific companions, and they apparently sought to alleviate it by broadening and strengthening their social relationships.     

B cell induction of IL-13 expression in NK cells: role of CD244 and SLAM-associated protein

NK cells are an important component of the innate immune system that can also interact with B cells in a mutually productive manner. We have previously shown that activated B cells can induce NK cells to up-regulate their secretion of IFN-gamma. In this study, we show that B cells, and, particularly, marginal zone B cells, can, in addition, induce NK cells via direct cell-cell interactions to express mRNA encoding the Th2 cytokine IL-13. The induction of NK cell IL-13 mRNA expression requires the ligation of the CD244 receptor by the CD48 ligand on B cells via signaling pathways that depend upon expression of the X-linked lymphoproliferative disease gene product, SH2D1A/DSHP/SAP (SLAM-associated protein, or SAP) in NK cells. Thus, the positive signals attributed to the B cell activation of CD244 on murine NK cells appears to be more similar to the activity of CD244 on human cells. The induction of IL-13 mRNA by B cells may account for the effect of NK cells on the generation of Th2-type responses in the presence of some adjuvants.     

Development of a carbohydrate binding assay for the B-oligomer of pertussis toxin and toxoid

Pertussis toxin (PTx) is a major virulence factor produced by Bordetella pertussis and, in its detoxified form PTd, is an important component of pertussis vaccines. The in vivo histamine sensitization test (HIST) is currently used for the safety testing of these vaccines. However, an alternative test is needed because of large assay variability and ethical concerns with regard to animal usage. PTx has two functionally distinct domains: the enzymatic A-protomer and the B-oligomer that facilitates host-cell binding and entry of PTx into the cell. The development of a quantitative PTx binding assay using glycoproteins or defined oligosaccharides is reported. PTx was found to bind preferentially to multiantennary N-glycans, with the highest binding toward the fully sialylated structures. In contrast, PTd lost the ability of PTx to bind to sialylated multiantennary structures but retained some capacity to bind to neutral multiantennary structures. The developed assay was shown to be specific, sensitive, and robust and could be used for investigating the mechanisms of PTx detoxification and for monitoring PTx binding activity in vaccine formulations. This assay could also be used to complement a PTx-enzymatic assay, developed recently, and together they may form the basis of a potential alternative in vitro assay to replace the in vivo HIST.     

Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility

Originally thought of as a stomach-derived endocrine peptide acting via its receptors in the central nervous system to stimulate food intake and growth hormone expression, ghrelin and its receptor (growth hormone secretagogue receptor (GHS-R)) are widely expressed in a number of organ systems, including cancer cells. However, the direct functional role of ghrelin and its receptor in tumors of central nervous system origin remains to be defined. Here, we demonstrate that the human astrocytoma cell lines U-118, U-87, CCF-STTG1, and SW1088 express 6-, 11-, 15-, and 29-fold higher levels of GHS-R compared with primary normal human astrocytes. The ligation of GHS-R by ghrelin on these cells resulted in an increase in intracellular calcium mobilization, protein kinase C activation, actin polymerization, matrix metalloproteinase-2 activity, and astrocytoma motility. In addition, ghrelin led to actin polymerization and membrane ruffling on cells, with the specific co-localization of the small GTPase Rac1 with GHS-R on the leading edge of the astrocytoma cells and imparting the tumor cells with a motile phenotype. Disruption of the endogenous ghrelin/GHS-R pathway by RNA interference resulted in diminished motility, matrix metalloproteinase activity, and Rac expression, whereas tumor cells stably overexpressing GHS-R exhibited increased cell motility. The relevance of ghrelin and GHS-R expression was verified in clinically relevant tissues from 20 patients with oligodendrogliomas and grade II-IV astrocytomas. Analysis of a central nervous system tumor tissue microarray revealed that strong GHS-R and ghrelin expression was significantly more common in high grade tumors compared with low grade ones. Together, these findings suggest a novel role for the ghrelin/GHS-R axis in astrocytoma cell migration and invasiveness of cancers of central nervous system origin.