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UnlabelledTranscription factors of the far-upstream element-binding protein (FBP) family represent cellular pathway hubs, and their overexpression in liver cancer (hepatocellular carcinoma [HCC]) stimulates tumor cell proliferation and correlates with poor prognosis. Here we determine the mode of oncogenic FBP overexpression in HCC cells. Using perturbation approaches (kinase inhibitors, small interfering RNAs) and a novel system for rapalog-dependent activation of AKT isoforms, we demonstrate that activity of the phosphatidylinositol-4,5-biphosphate 3-kinase/AKT pathway is involved in the enrichment of nuclear FBP1 and FBP2 in liver cancer cells. In human HCC tissues, phospho-AKT significantly correlates with nuclear FBP1/2 accumulation and expression of the proliferation marker KI67. Mechanistic target of rapamycin (mTOR) inhibition or blockade of its downstream effector eukaryotic translation initiation factor 4E activity equally reduced FBP1/2 concentrations. The mTORC1 inhibitor rapamycin diminishes FBP enrichment in liver tumors after hydrodynamic gene delivery of AKT plasmids. In addition, the multikinase inhibitor sorafenib significantly reduces FBP levels in HCC cells and in multidrug resistance 2-deficient mice that develop HCC due to severe inflammation. Both FBP1/2 messenger RNAs are highly stable, with FBP2 being more stable than FBP1. Importantly, inhibition of phosphatidylinositol-4,5-biphosphate 3-kinase/AKT/mTOR signaling significantly diminishes FBP1/2 protein stability in a caspase-3/-7-dependent manner.ConclusionThese data provide insight into a transcription-independent mechanism of FBP protein enrichment in liver cancer; further studies will have to show whether this previously unknown interaction between phosphatidylinositol-4,5-biphosphate 3-kinase/AKT/mTOR pathway activity and caspase-mediated FBP stabilization allows the establishment of interventional strategies in FBP-positive HCCs.

Abstract Background Patients with diabetes already fulfill one diagnostic criterion for MS according to the existing classifications. Our aim was to identify one single clinical parameter, which could effectively predict the presence of MS in patients with type 2 diabetes. Methods We studied all patients with type 2 diabetes who attended our Diabetes Outpatient Clinic during a three-month period. Waist circumference, blood pressure and serum lipids were measured. Establishment of MS diagnosis was based a) on National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria and b) on International Diabetes Federation (IDF) criteria. Receiver operating characteristic (ROC) analysis was applied in order to identify the clinical parameter with the highest predictive capability for MS. Among the 500 participating patients (231 males, 269 females), MS was diagnosed in 364 patients (72.8%) according to the NCEP ATP III criteria and in 408 patients (81.6%) according to the IDF criteria. Results For the NCEP ATP III classification, serum triglycerides (in the overall population), waist and HDL (in female population) demonstrated the highest predictive capability for MS (AUCs:0.786, 0.805 and 0.801, respectively). For the IDF classification, no single parameter reached an AUC > 0.800 in the overall population. In females, HDL displayed a satisfactory predictive capability for MS with an AUC which was significantly higher than the one in males (0.785 vs. 0.676, respectively, p < 0.05). Conclusion Elevated serum triglycerides strongly indicate the presence of MS in patients with type 2 diabetes. In female patients with type 2 diabetes, central obesity was the second stronger predictor of MS besides hypertriglyceridemia.

FGF2 is exported from cells by an unconventional secretory mechanism. Here, we directly visualized individual FGF2 membrane translocation events at the plasma membrane using live cell TIRF microscopy. This process was dependent on both PI(4,5)P2-mediated recruitment of FGF2 at the inner leaflet and heparan sulfates capturing FGF2 at the outer plasma membrane leaflet. By simultaneous imaging of both FGF2 membrane recruitment and the appearance of FGF2 at the cell surface, we revealed the kinetics of FGF2 membrane translocation in living cells with an average duration of ~200 ms. Furthermore, we directly demonstrated FGF2 oligomers at the inner leaflet of living cells with a FGF2 dimer being the most prominent species. We propose this dimer to represent a key intermediate in the formation of higher FGF2 oligomers that form membrane pores and put forward a kinetic model explaining the mechanism by which membrane-inserted FGF2 oligomers serve as dynamic translocation intermediates during unconventional secretion of FGF2. [ABSTRACT FROM AUTHOR]

Abstract: Interaction between mGluR5 and NMDA receptors (NMDAR) is vital for synaptic plasticity and cognition. We recently demonstrated that stimulation of mGluR5 enhances NMDAR responses in hippocampus by phosphorylating NR2B(Tyr1472) subunit, and this reaction was enabled by adenosine A2A receptors (A2AR) (J Neurochem, 135, 2015, 714). In this study, by using in vitro phosphorylation and western blot analysis in hippocampal slices of male Wistar rats, we show that mGluR5 stimulation or mGluR5/NMDARs co‐stimulation synergistically activate ERK1/2 signaling leading to c‐Fos expression. Interestingly, both reactions are under the permissive control of endogenous adenosine acting through A2ARs. Moreover, mGluR5‐mediated ERK1/2 phosphorylation depends on NMDAR, which however exhibits a metabotropic way of function, since no ion influx through its ion channel is required. Furthermore, our results demonstrate that mGluR5 and mGluR5/NMDAR‐evoked ERK1/2 activation correlates well with the mGluR5/NMDAR‐evoked NR2B(Tyr1472) phosphorylation, since both phenomena coincide temporally, are Src dependent, and are both enabled by A2ARs. This indicates a functional involvement of NR2B(Tyr1472) phosphorylation in the ERK1/2 activation. Our biochemical results are supported by electrophysiological data showing that in CA1 region of hippocampus, the theta burst stimulation (TBS)‐induced long‐term potentiation coincides temporally with an increase in ERK1/2 activation and both phenomena are dependent on the tripartite A2A, mGlu5, and NMDARs. Furthermore, we show that the dopamine D1 receptors evoked ERK1/2 activation as well as the NR2B(Tyr1472) phosphorylation are also regulated by endogenous adenosine and A2ARs. In conclusion, our results highlight the A2ARs as a crucial regulator not only for NMDAR responses, but also for regulating ERK1/2 signaling and its downstream pathways, leading to gene expression, synaptic plasticity, and memory consolidation. [ABSTRACT FROM AUTHOR]

This paper demonstrates that subcultural theory continues to provide a relevant and useful analysis of youth leisure practices and their political significance in contemporary society. It achieves this by analysing the theoretical antecedents to both subcultural theory and the post-subcultural theory that followed it. It is argued that the post-subcultural turn to studying affects and everyday lives resonates deeply with the Gramscian perspective informing subcultural theory. It is thus possible to interpret post-subculturalism as augmenting rather than negating its predecessor. Deploying an analysis that combines these perspectives allows for an account of contemporary youth leisure practices that demonstrates a number of different forms of politics explicated within the paper: a politics of identity and becoming; a politics of defiance; a politics of affective solidarity and a politics of different experience. Whilst not articulated or necessarily conscious, there is a proto-politics to youth leisure that precludes it from being dismissed as entirely empty, hedonistic and consumerist. This paper demonstrates how the lens of post-subculturalism focuses on the affective spaces where this politics is most apparent and provides a means of updating subcultural theory to understand contemporary youth practices. [ABSTRACT FROM PUBLISHER]

Secondary rectal linitis plastica is a very rare malignancy with poor prognosis. Diagnosis is difficult because of nonspecific clinical and endoscopic findings and negative biopsies in most cases owing to the fact that the mucosa is frequently unaffected. We herein describe a 68-year-old man who presented with a six-month history of tenesmus and constipation. Endoscopy revealed a narrow distal rectum with an indurated, cobblestone appearance of mucosa. Multiple biopsies and fine-needle aspiration were negative for malignancy. Abdominal MRI and transrectal ultrasonography showed findings compatible with rectal linitis plastica. He underwent rectal extirpation with total cystectomy and lymph nodes dissection. Histology demonstrated secondary rectal linitis plastica due to a poorly differentiated urinary bladder carcinoma. We emphasize the endoscopic and endosonographic features and the difficulty to establish a preoperative diagnosis of secondary rectal linitis plastica. [ABSTRACT FROM AUTHOR]

Mesenteric panniculitis (MP) is a rare inflammatory and fibrotic disease of the mesentery of unknown etiology. It has various clinical and radiological manifestations, posing a diagnostic challenge for clinicians. Its diagnosis is indicated via radiologic imaging and is usually confirmed via peritoneal biopsies. We describe a case of a patient with histopathologically proven MP, in which steroid dependence was successfully managed with colchicine. [ABSTRACT FROM AUTHOR]