Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification.

Smoking-related cues elicit craving and mesocorticolimbic brain activation in smokers. Severity of nicotine dependence seems to moderate cue reactivity, but the direction and mechanisms of its influence remains unclear. Although tobacco control policies demand a ban on tobacco advertising, cue reactivity studies in smokers so far have not employed tobacco advertisement as experimental stimuli. We investigated whether tobacco advertisement elicits cue reactivity at a behavioral (subjective craving) and a neural level (using functional magnetic resonance imaging) in 22 smokers and 21 never-smokers. Moreover, we studied the influence of severity of dependence on cue reactivity. In smokers, tobacco advertisement elicited substantially more craving than control advertisement whereas never-smokers reported no cue induced craving. Surprisingly, neuronal cue reactivity did not differ between smokers and never-smokers. Moderately dependent smokers' craving increased over the course of the experiment, whereas highly dependent smokers' craving was unaffected. Moderately dependent smokers' brain activity elicited by tobacco advertisement was higher in the amygdala, hippocampus, putamen and thalamus compared with highly dependent smokers. Furthermore, limbic brain activation predicted picture recognition rates after the scanning session, even in never-smokers. Our findings show that tobacco advertisement elicits cigarette craving and neuronal cue reactivity primarily in moderately dependent smokers, indicating that they might be particularly responsive towards external smoking-related cues. On the other hand, neuronal cue reactivity and cigarette craving in highly dependent smokers is more likely triggered by internal cues such as withdrawal symptoms. Tobacco advertisement seems to likewise appeal to smokers and non-smokers, clarifying the potential danger especially for young non-smokers.

Objectives:The aim of this cross-sectional study was to investigate whether sex hormones (testosterone, oestradiol, sex-hormone-binding globulin = SHBG) are associated with general joint laxity (GJL) and hypermobility or derangements of the temporomandibular joint (TMJ) in adolescents. Methods:Within the LIFE Child study, 970 adolescents (10-18 years) were included.GJL was assessed using the Beighton test. Maximum mouth opening (MMO) and clinical clicking sounds as signs of disc displacement (DD) in the TMJ were assessed according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD).Serum levels of sex hormones were assessed using standardised laboratory analyses.Results: Hypermobile joints were found in 54.9% (N = 532) of the sample; females were more affected than males (61.4% vs. 51.8%, P < 0.001). Using logistic regression analyses, the odds ratio (OR) for having >1 hypermobile joints increased to 1.15 (95% confidence interval [CI]: 1.04-1.27) in males and 1.09 (95% CI: 1.02-1.17) in females per 10 units of the SHBG serum level, compared to those without hypermobile joints-after controlling for the effect of age, adjusted BMI, pubertal development (Tanner scale), testosterone as well as oestradiol levels. Female subjects with >1 hypermobile joints showed a higher OR (1.89; 95% CI: 1.05-3.43) for having clinical clicking sounds in the TMJ and a 3.28 times higher OR (95% CI: 1.44-7.44) for MMO ≥ 55 mm. Conclusions:We observed age-and gender-independent associations of higher SHBG serum levels with GJL in adolescents. Moreover, hypermobile female adolescents show a more frequent hypermobility of the TMJ and clinical signs of DD. K E Y W O R D Sadolescents, general joint laxity, hypermobility, sex hormones, temporomandibular disorders

Dopamine (DA) modulates the response of the amygdala. However, the relation between dopaminergic neurotransmission in striatal and extrastriatal brain regions and amygdala reactivity to affective stimuli has not yet been established. To address this issue, we measured DA D2/D3 receptor (DRD2/3) availability in twenty-eight healthy men (nicotine-dependent smokers and never-smokers) using positron emission tomography with [ 18 F]fallypride. In the same group of participants, amygdala response to unpleasant visual stimuli was determined using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. The effects of DRD2/3 availability in emotion-related brain regions and nicotine dependence on amygdala response to unpleasant stimuli were examined by multiple regression analysis. We observed enhanced prefrontal DRD2/3 availability in those individuals with higher amygdala response to unpleasant stimuli. As compared to never-smokers, smokers showed an attenuated amygdala BOLD response to unpleasant stimuli. Thus, individuals with high prefrontal DRD2/3 availability may be more responsive toward aversive and stressful information. Through this mechanism, dopaminergic neurotransmission might influence vulnerability for affective and anxiety disorders. Neuronal reactivity to unpleasant stimuli seems to be reduced by smoking. This observation could explain increased smoking rates in individuals with mental disorders. Hum Brain Mapp 31:716-726,