Prognostic variables in surgery for skull base meningiomas

Journal ArticleThe authors have retrospectively analyzed selected surgical and pathological observations made among a group of 20 patients harboring recurrent cranial base meningiomas in an attempt to reveal which factors may be important in predicting tumor recurrence. This cohort was compared with a group of 34 patients with cranial base meningiomas that underwent primary resection and in whom tumor recurrence has not been demonstrated over a median follow-up period of 33 months. Features analyzed included brain, cranial nerve, carotid artery, or muscle invasion as well as tumor cellularity, nucleolar prominence, cellular pleomorphism, and percentage of cells staining positive for the Ki-67 antigen. As expected, increased cellularity and tumor necrosis were relatively more prevalent in recurrent tumors. With regard to tumor type, atypical and anaplastic tumors were more common in the group of patients with recurrent tumor compared with the primary group (p < 0.02). As expected, increased cellularity was relatively more prominent in recurrent tumors. Invasion of muscle and bone (72%) was more frequently associated with recurrent tumors, suggesting that these characteristics may be important features of recurrent skull base meningiomas

Active bacterial core surveillance of the emerging infections program network.

Active Bacterial Core surveillance (ABCs) is a collaboration between the Centers for Disease Control and Prevention and several state health departments and universities participating in the Emerging Infections Program Network. ABCs conducts population-based active surveillance, collects isolates, and performs studies of invasive disease caused by Streptococcus pneumoniae, group A and group B Streptococcus, Neisseria meningitidis, and Haemophilus influenzae for a population of 17 to 30 million. These pathogens caused an estimated 97,000 invasive cases, resulting in 10,000 deaths in the United States in 1998. Incidence rates of these pathogens are described. During 1998, 25% of invasive pneumococcal infections in ABCs areas were not susceptible to penicillin, and 13.3% were not susceptible to three classes of antibiotics. In 1998, early-onset group B streptococcal disease had declined by 65% over the previous 6 years. More information on ABCs is available at www.cdc.gov/ncidod/dbmd/abcs. ABCs specimens will soon be available to researchers through an archive

Comparative Analysis of the Heptahelical Transmembrane Bundles of G Protein-Coupled Receptors

Background: G protein-coupled receptors represent a large family of eukaryotic membrane proteins, and are involved in almost all physiological processes in humans. Recent advances in the crystallographic study of these receptors enable a detailed comparative analysis of the commonly shared heptahelical transmembrane bundle. Systematic comparison of the bundles from a variety of receptors is indispensable for understanding not only of the structural diversification optimized for the binding of respective ligands but also of the structural conservation required for the common mechanism of activation accompanying the interaction changes among the seven helices. Methodology/Principal Findings: We have examined the bundles of 94 polypeptide chains from almost all available structures of 11 receptors, which we classified into either inactivated chain or activated chain, based on the type of bound ligand. For the inactivated chains, superposition of 200 residue bundles by secondary structure matching demonstrated that the bound ligands share a laterally limited cavity in the extracellular section of the bundle. Furthermore, a distinct feature was found for helix III of bovine rhodopsin, which might have evolved to lower its activity in the presence of 11-cis-retinal, to a level that other receptors could hardly achieve with any currently available ligands. Conclusions/Significance: Systematic analysis described here would be valuable for understanding of the rearrangement o

An Essential Role of the Cytoplasmic Tail of CXCR4 in G-Protein Signaling and Organogenesis

CXCR4 regulates cell proliferation, enhances cell survival and induces chemotaxis, yet molecular mechanisms underlying its signaling remain elusive. Like all other G-protein coupled receptors (GPCRs), CXCR4 delivers signals through G-protein-dependent and -independent pathways, the latter involving its serine-rich cytoplasmic tail. To evaluate the signaling and biological contribution of this G-protein-independent pathway, we generated mutant mice that express cytoplasmic tail-truncated CXCR4 (ΔT) by a gene knock-in approach. We found that ΔT mice exhibited multiple developmental defects, with not only G-protein-independent but also G-protein-dependent signaling events completely abolished, despite ΔT's ability to still associate with G-proteins. These results reveal an essential positive regulatory role of the cytoplasmic tail in CXCR4 signaling and suggest the tail is crucial for mediating G-protein activation and initiating crosstalk between G-protein-dependent and G-protein-independent pathways for correct GPCR signaling

CXCL12 and [N33A]CXCL12 in 5637 and HeLa Cells: Regulating HER1 Phosphorylation via Calmodulin/Calcineurin

In the human neoplastic cell lines 5637 and HeLa, recombinant CXCL12 elicited, as expected, downstream signals via both G-protein-dependent and β-arrestin-dependent pathways responsible for inducing a rapid and a late wave, respectively, of ERK1/2 phosphorylation. In contrast, the structural variant [N33A]CXCL12 triggered no β-arrestin-dependent phosphorylation of ERK1/2, and signaled via G protein-dependent pathways alone. Both CXCL12 and [N33A]CXCL12, however, generated signals that transinhibited HER1 phosphorylation via intracellular pathways. 1) Prestimulation of CXCR4/HER1-positive 5637 or HeLa cells with CXCL12 modified the HB-EGF-dependent activation of HER1 by delaying the peak phosphorylation of tyrosine 1068 or 1173. 2) Prestimulation with the synthetic variant [N33A]CXCL12, while preserving CXCR4-related chemotaxis and CXCR4 internalization, abolished HER1 phosphorylation. 3) In cells knockdown of β-arrestin 2, CXCL12 induced a full inhibition of HER1 like [N33A]CXCL12 in non-silenced cells. 4) HER1 phosphorylation was restored as usual by inhibiting PCK, calmodulin or calcineurin, whereas the inhibition of CaMKII had no discernable effect. We conclude that both recombinant CXCL12 and its structural variant [N33A]CXCL12 may transinhibit HER1 via G-proteins/calmodulin/calcineurin, but [N33A]CXCL12 does not activate β-arrestin-dependent ERK1/2 phosphorylation and retains a stronger inhibitory effect. Therefore, we demonstrated that CXCL12 may influence the magnitude and the persistence of signaling downstream of HER1 in turn involved in the proliferative potential of numerous epithelial cancer. In addition, we recognized that [N33A]CXCL12 activates preferentially G-protein-dependent pathways and is an inhibitor of HER1

Ligand-Induced Modulation of the Free-Energy Landscape of G Protein-Coupled Receptors Explored by Adaptive Biasing Techniques

Extensive experimental information supports the formation of ligand-specific conformations of G protein-coupled receptors (GPCRs) as a possible molecular basis for their functional selectivity for signaling pathways. Taking advantage of the recently published inactive and active crystal structures of GPCRs, we have implemented an all-atom computational strategy that combines different adaptive biasing techniques to identify ligand-specific conformations along pre-determined activation pathways. Using the prototypic GPCR β2-adrenergic receptor as a suitable test case for validation, we show that ligands with different efficacies (either inverse agonists, neutral antagonists, or agonists) modulate the free-energy landscape of the receptor by shifting the conformational equilibrium towards active or inactive conformations depending on their elicited physiological response. Notably, we provide for the first time a quantitative description of the thermodynamics of the receptor in an explicit atomistic environment, which accounts for the receptor basal activity and the stabilization of different active-like states by differently potent agonists. Structural inspection of these metastable states reveals unique conformations of the receptor that may have been difficult to retrieve experimentally