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It is unclear whether deviations in brain and behavioral development, which may underpin elevated substance use during adolescence, are predispositions for or consequences of substance use initiation. Here, we examine behavioral and neuroimaging indices at early and mid-adolescence in drug-naive youths to identify possible predisposing factors for substance use initiation and its possible consequences.Among 304 drug-naive adolescents at baseline (age 14 years) from the IMAGEN dataset, 83 stayed drug-naive, 133 used alcohol on 1 to 9 occasions, 42 on 10 to 19 occasions, 27 on 20 to 39 occasions, and 19 on40 occasions at follow-up (age 16 years). Baseline measures included brain activation during the Monetary Incentive Delay task. Data at both baseline and follow-up included measures of trait impulsivity and delay discounting.From baseline to follow-up, impulsivity decreased in the 0 and 1- to 9-occasions groups (p .004), did not change in the 10- to 19-occasions and 20- to 29-occasions groups (p.294), and uncharacteristically increased in the40-occasions group (p = .046). Furthermore, blunted medial orbitofrontal cortex activation during reward outcome at baseline significantly predicted higher alcohol use frequency at follow-up, above and beyond behavioral and clinical variables (p = .008).These results suggest that the transition from no use to frequent drinking in early to mid-adolescence may disrupt normative developmental changes in behavioral control. In addition, blunted activity of the medial orbitofrontal cortex during reward outcome may underscore a predisposition toward the development of more severe alcohol use in adolescents. This distinction is clinically important, as it informs early intervention efforts in preventing the onset of substance use disorder in adolescents.

Objective Irritable mood, a common and impairing symptom in psychopathology, has been proposed to underlie the developmental link between oppositional problems in youth and depression in adulthood. We examined the neural correlates of adolescent irritability in IMAGEN, a sample of 2,024 14-year-old adolescents from 5 European countries. Method The Development and Well-Being Assessment (DAWBA) was used to assess attention-deficit/hyperactivity disorder, major depressive disorder, oppositional defiant disorder, and generalized anxiety disorder. Three items from the DAWBA, selected as close matches to the Affective Reactivity Index, were used to assess irritability. Structural magnetic resonance imaging was examined using whole-brain voxel-based morphometry analysis, and functional magnetic resonance imaging was examined during a stop signal task of inhibitory control. Imaging data were included in structural equation models to examine the direct and indirect associations between irritable mood and comorbid DSM diagnoses. Results Whole-brain voxelwise analysis showed that adolescent irritable mood was associated with less gray matter volume and less neural activation underlying inhibitory control in frontal and temporal cortical areas (cluster-correction at p Conclusion This study identifies adolescent irritability as an independent construct and points to a neurobiological correlate to irritability that is an important contributing feature to many psychopathological disorders.

Activating mutations in genes encoding receptor tyrosine kinases (RTKs) mediate proliferation, cell migration, and cell survival, and are therefore important drivers of oncogenesis. Numerous targeted cancer therapies are directed against activated RTKs, including small compound inhibitors, and immunotherapies. It has recently been discovered that not only certain RTK fusion proteins, but also many full-length RTKs harbouring activating mutations, notably RTKs of the class III family, are to a large extent mislocalised in intracellular membranes. Active kinases in these locations cause aberrant activation of signalling pathways. Moreover, low levels of activated RTKs at the cell surface present an obstacle for immunotherapy. We outline here why understanding of the mechanisms underlying mislocalisation will help in improving existing and developing novel therapeutic strategies.

Background Studying the neural consequences of tobacco smoking during adolescence, including those associated with early light use, may help expose the mechanisms that underlie the transition from initial use to nicotine dependence in adulthood. However, only a few studies in adolescents exist, and they include small samples. In addition, the neural mechanism, if one exists, that links nicotinic receptor genes to smoking behavior in adolescents is still unknown. Methods Structural and diffusion tensor magnetic resonance imaging data were acquired from a large sample of 14-year-old adolescents who completed an extensive battery of neuropsychological, clinical, personality, and drug-use assessments. Additional assessments were conducted at 16 years of age. Results Exposure to smoking in adolescents, even at low doses, is linked to volume changes in the ventromedial prefrontal cortex and to altered neuronal connectivity in the corpus callosum. The longitudinal analyses strongly suggest that these effects are not preexisting conditions in those who progress to smoking. There was a genetic contribution wherein the volume reduction effects were magnified in smokers who were carriers of the high-risk genotype of the alpha 5 nicotinic receptor subunit gene, rs16969968. Conclusions These findings give insight into a mechanism involving genes, brain structure, and connectivity underlying why some adolescents find nicotine especially addictive.

SummaryInterleukin 6 (IL-6) is a pleiotropic four-helix-bundle cytokine that exerts multiple functions in the body. In the liver, IL-6 is an important inducer of the acute phase response and infection defense. IL-6 is furthermore crucial for hepatocyte homeostasis and is a potent hepatocyte mitogen. It is not only implicated in liver regeneration, but also in metabolic function of the liver. However, persistent activation of the IL-6 signaling pathway is detrimental to the liver and might ultimately result in the development of liver tumors. On target cells IL-6 can bind to the signal transducing subunit gp130 either in complex with the membrane-bound or with the soluble IL-6 receptor to induce intracellular signaling. In this review we describe how these different pathways are involved in the physiology and pathophyiology of the liver. We furthermore discuss how IL-6 pathways can be selectively inhibited and therapeutically exploited for the treatment of liver pathologies.

When handling flammable and/or toxic liquids or gases, the gas dispersion following a release of substance is a scenario to be considered in the risk assessment to determine the lower flammability distance (LFD) and toxicity thresholds. In this work a comparison of different gas dispersion tools of varying complexity ranging from a simple Gaussian model over a boundary layer model (BLM) and a Lagrangian model to CFD (in this case ANSYS CFX v14) is presented. The BLM covers the special case of liquid releases with formation of a pool. It does not only solve the gas dispersion but also calculates the evaporating mass flow out of the pool. The simulation values are compared to each other and to experimental data resulting mainly from our own open air experiments covering the near field and carried out on the Test Site Technical Safety of BAM (BAM-TTS) for different release types (pool evaporation, gas release) and topologies. Other validation data were taken from literature and cover large scale experiments in the range of several 100 m.

Interleukin-6 is a cytokine not only involved in inflammation and infection responses but also in the regulation of metabolic, regenerative, and neural processes. In classic signaling, interleukin-6 stimulates target cells via a membrane bound interleukin-6 receptor, which upon ligand binding associates with the signaling receptor protein gp130. Gp130 dimerizes, leading to the activation of Janus kinases and subsequent phosphorylation of tyrosine residues within the cytoplasmic portion of gp130. This leads to the engagement of phosphatase Src homology domains containing tyrosin phosphatase-2 (SHP-2) and activation of the ras/raf/Mitogen-activated protein (MAP) kinase (MAPK) pathway. In addition, signal transducer and activator of transcription factors are recruited, which are phosphorylated, and consequently dimerize whereupon they translocate into the nucleus and activate target genes. Interestingly, only few cells express membrane bound interleukin-6 receptor whereas all cells display gp130 on the cell surface. While cells, which only express gp130, are not responsive to interleukin-6 alone, they can respond to a complex of interleukin-6 bound to a naturally occurring soluble form of the interleukin-6 receptor. Therefore, the generation of soluble form of the interleukin-6 receptor dramatically enlarges the spectrum of interleukin-6 target cells. This process has been named trans-signaling. Here, we review the involvement of both signaling modes in the biology of interleukin-6. It turns out that regenerative or anti-inflammatory activities of interleukin-6 are mediated by classic signaling whereas pro-inflammatory responses of interleukin-6 are rather mediated by trans-signaling. This is important since therapeutic blockade of interleukin-6 by the neutralizing anti-interleukin-6 receptor monoclonal antibody tocilizumab has recently been approved for the treatment of inflammatory diseases. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.

Two novel classes of non-steroidal substrate mimetics were synthesised and examined for their potency as inhibitors of human CYP17. Selected compounds were tested for inhibition of hepatic CYP enzymes 3A4, 1A2, 2C9 and 2C19. The most promising compound 15 showed a good inhibition of the target enzyme (31% and 66% at 0.2 and 2 microM, respectively), and little inhibition of the most important hepatic enzyme CYP3A4 (6% and 19% inhibition at 0.2 and 2 microM, respectively) and the key enzyme of glucocorticoid biosynthesis CYP11B1 (3% and 23% inhibition at 0.2 and 2 microM, respectively). Docking studies revealed that this compound does not assume the same binding mode as steroidal ligands.

We recently described that in the metastasizing rat pancreatic carcinoma line BSp73ASML the cell-cell adhesion molecule EpCAM, CD44 variant isoforms and the tetraspanins D6.1A and CD9 form a complex that is located in glycolipid-enriched membrane microdomains. This complex contains, in addition, an undefined 20 kDa protein. As such complex formation influenced cell-cell adhesion and apoptosis resistance, it became of interest to identify the 20 kDa polypeptide. This 20 kDa protein, which co-precipitated with EpCAM in BSp73ASML lysates, was identified as the tight junction protein claudin-7. Correspondingly, an association between EpCAM and claudin-7 was noted in rat and human tumors and in non-transformed tissues of the gastrointestinal tract. Co-localization of the two molecules was most pronounced at basolateral membranes, but was also observed in tight junctions. Evidence for direct protein-protein interactions between EpCAM and claudin-7 was obtained by co-immunoprecipitation after treatment of tumor cells with a membrane-permeable chemical cross-linker. The complex, which is located in glycolipid-enriched membrane microdomains, is not disrupted by partial cholesterol depletion, but claudin-7 phosphorylation is restricted to the localization in glycolipid-enriched membrane microdomains. This is the first report on an association between EpCAM and claudins in both non-transformed tissues and metastasizing tumor cell lines.

Conventional extracorporeal circulation results in an activation of coagulation cascades. Coating of extracorporeal circulation tubes as well as avoidance of shed blood recirculation have been shown to reduce these phenomena. We evaluated a new shed blood separation system (AVANT D 970) utilizing a coated cardiopulmonary bypass tube system (PHISIO).Forty patients (62 +/- 10 years) underwent isolated coronary revascularization. Four groups (n = 10/group) were defined: no extracorporeal circulation, conventional uncoated extracorporeal circulation, uncoated extracorporeal circulation with shed blood separation, and coated extracorporeal circulation with shed blood separation. Thrombin-antithrombin complex and free Hb were analyzed and statistically compared.Conventional extracorporeal circulation exhibited the highest intraoperative activation of coagulation (thrombin-antithrombin complex: extracorporeal circulation, 31.1 +/- 15.8 microg/L; uncoated extracorporeal circulation with shed blood separation, 15.3 +/- 7.8 microg/L; coated extracorporeal circulation with shed blood separation, 8.1 +/- 4.8 microg/L; no extracorporeal circulation, 2.4 +/- 0.6 microg/L; P.05 extracorporeal circulation vs all others) and red blood cell damage (free Hb: extracorporeal circulation, 16.8 +/- 11.4 micromol/L; uncoated extracorporeal circulation with shed blood separation, 10.3 +/- 3.5 micromol/L; coated extracorporeal circulation with shed blood separation, 6.8 +/- 2.9 micromol/L; no extracorporeal circulation, 3.4 +/- 1.1 micromol/L; P.05 extracorporeal circulation vs no extracorporeal circulation, coated extracorporeal circulation with shed blood separation). Coated extracorporeal circulation with shed blood separation showed only slight activation and cell trauma, which did not differ significantly from no extracorporeal circulation.Combination of coating and avoidance of shed blood recirculation maintained physiological coagulation levels and markedly reduced red blood cell trauma in extracorporeal circulation procedures. These combined modalities may therefore offer an alternative for off-pump procedures in patients with contraindications for conventional extracorporeal circulation.

The role of higher chitooligomers in medical applications is increasing due to their interesting biological activities. Transglycosylation activity of β-N-acetylhexosaminidase from Aspergillus oryzae was employed to produce higher chitooligosaccharides (chitohexaose–chitooctaose) from a mixture of lower chitooligomers prepared by acid hydrolysis of chitin. Enzymatic rearrangement of the chitooligomer mixture was optimized in respect of substrate concentration, presence of inorganic salts, enzyme activity, and reaction time to achieve the highest production of longer chitooligomers.

Background and Aims: Transforming growth factor (TGF)-b is a ubiquitously expressed cytokine with fundamental roles in various aspects of cell physiology. In carcinogenesis, TGF-b signaling plays a dual role. While it suppresses the proliferation of epithelial cells and adenoma cells at early stages by inducing growth arrest and apoptosis, it triggers epithelial to mesenchymal transition (EMT) and gain of metastatic abilities at later stages of carcinoma development. The molecular mechanisms underlying this ’TGF-bswitch’ are only beginning to be unravelled. To mimic the pathophysiological situation as closely as possible, we exposed the cells to TGFb long-term. Through this approach we aimed to identify those cooperating factors and signaling pathways that cause HCC cells to interpret the TGF-b signal in a tumor progressive way. Methods: In vitro comparison of migratory behaviour of various HCC cell lines treated long-term (>10 days) with TGF-b. Analysis of regulatory networks and target genes underlying the TGF-b treatment. Results: HCC cell lines that have undergone EMT secrete TGF-b and show elevated levels of Smad2/3 phosphorylation indicating an autocrine regulatory feedback loop. Inhibition of TGF-b by LY2109 abrogates autocrine stimulation and diminishes the migratory potential of mesenchymal HCC cells. Silencing of either TGF-bR1 or Smad4 indicated the importance of canonical TGF-b/Smad signaling HCC cell migration. Short-term treatment of cells with TGF-b could not improve migratory abilities. Interestingly, long-term TGF-b treatment revealed crucial differences between mesenchymal HCC cell lines. While HLF cells showed an increase in migration when treated with TGF-b for more than 10 days, SNU449 displayed a dramatic reduction in migration. However, both cell lines displayed no modulation in Smad phosphorylation, indicating a change in the utilization of TGF-b signaling in long-term treated SNU449 cells. Conclusions: EMT-transformed HCC cells establish an autocrine TGF-b loop which stimulates migration. However, TGF-b cannot add up to the autocrine loop but causes a different, even opposing reaction, over time. Interpretation of long-term TGF-b signaling, which mimics the patient’s situation more closely, depends on duration and intensity and is controlled by co-acting factors and signaling pathways. P0301 Withdrawn

Objective Functional magnetic resonance imaging (fMRI) studies have identified increased amygdala responses to negative stimuli as a risk marker of depression in adults, and as a state marker of depression in adults and adolescents. Hyperreactivity of the amygdala has been linked to negatively biased emotional processing in depression. However, no study has elucidated whether similar amygdala perturbations can be found in healthy mid-adolescents with familial liability for depression. We hypothesized that healthy 14-year-olds with relatives with depression would demonstrate increased amygdala responses to negative stimuli, as compared with their peers with no family history of mental disorders. Method We investigated a community-based sample of 164 typically developing 14-year-olds without record of past or current mental disorders. Of these individuals, 28 fulfilled criteria for family history of depression, and 136 served as controls. Groups did not differ with regard to cognitive ability, depressive symptomatology, and anxiety. During fMRI they performed a perceptual discrimination task in which visual target and distractor stimuli varied systematically with regard to emotional valence. Results Both a hypothesis-driven region-of-interest analysis and a whole-brain analysis of variance revealed that negative distractors elicited greater amygdala activation in adolescents with a family history of depression compared to controls. Amygdala responses also differed during the processing of negative target stimuli, but effects were reversed. Conclusion Our study demonstrates that familial liability for depression is associated with correlates of negatively biased emotional processing in healthy adolescents. Amygdala perturbations during the processing of negative stimuli might reflect an early and subtle risk marker for depression.