A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies

Extensive crosstalk among ErbB/HER receptors suggests that blocking signaling from more than one family member may be essential to effectively treat cancer and limit drug resistance. We generated a conventional IgG molecule MEHD7945A with dual HER3/EGFR specificity by phage display engineering and used structural and mutational studies to understand how a single antigen recognition surface binds two epitopes with high affinity. As a human IgG1, MEHD7945A exhibited dual action by inhibiting EGFR- and HER3-mediated signaling in?vitro and in?vivo and the ability to engage immune effector functions. Compared with monospecific anti-HER antibodies, MEHD7945A was more broadly efficacious in multiple tumor models, showing that combined inhibition of EGFR and HER3 with a single antibody is beneficial.     

A specific attentional bias in panic disorder?

According to cognitive theories, panic patients are assumed to have an attentional bias toward bodily sensations. To date, there is only some indirect evidence of such a bias measured by an emotional Stroop task. Moreover, the content and disorder specificity of this bias is rather unclear. The aim of this study was to investigate the specificity of attentional bias in patients with panic disorder (PD). Patients with PD (n=32), patients with mixed anxiety disorders (n=25), and a healthy control group (n=26) performed an emotional Stroop task with three word types: panic threat, general threat, and neutral. There were no differences on reaction times between the different groups, or on the different word types. Despite the generally accepted existence of attentional biases in anxiety disorders, we found no evidence of a specific attentional bias in patients with PD.     

Cooperation of the proapoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts

Recombinant human rhApo2L/TRAIL selectively stimulates apoptosis in various cancer cells through its receptors DR4 and DR5, and is currently in clinical trials. Preclinical studies have established antitumor activity of rhApo2L/TRAIL in models of epithelial cancers; however, efficacy in non-Hodgkin lymphoma (NHL) models is not well studied. Of 7 NHL cell lines tested in vitro, rhApo2L/TRAIL stimulated apoptosis in BJAB, Ramos RA1, and DoHH-2 cells. Rituximab, a CD20 antibody used to treat certain types of NHL, augmented rhApo2L/TRAIL-induced caspase activation in Ramos RA1 and DoHH2 but not BJAB or SC-1 cells, through modulation of intrinsic rather than extrinsic apoptosis signaling. In vivo, rhApo2L/TRAIL and rituximab cooperated to attenuate or reverse growth of tumor xenografts of all 4 of these cell lines. Depletion of natural killer (NK) cells or serum complement substantially reduced combined efficacy against Ramos RA1 tumors, suggesting involvement of antibody-dependent cell- and complement-mediated cytotoxicity. Both agents exhibited greater activity against disseminated than subcutaneous BJAB xenografts, and worked together to inhibit or abolish disseminated tumors and increase survival. Moreover, rhApo2L/TRAIL helped circumvent acquired rituximab resistance of a Ramos variant. These findings provide a strong rationale for clinical investigation of rhApo2L/TRAIL in combination with rituximab as a novel strategy for NHL therapy.     

Endothelial precursor cell migration during vasculogenesis

Migration of endothelial precursor cells (so-called "angioblasts" in embryos and "endothelial progenitor cells" in adults) during vasculogenesis is a requirement for the formation of a primary vascular plexus. The migration is initiated by the change of endothelial precursors to their migratory phenotype. The endothelial precursor cells are then guided to the position where the primary vascular plexus is formed. Migration is stopped by the reversion of the cells to their nonmigratory phenotype. A combination of regulatory mechanisms and factors controls this process. These include gradients of soluble factors, extracellular matrix-cell interaction and cell-cell interaction. In this review, we give an overview of the regulation of angioblast migration during embryonic vasculogenesis and its relationship to the migration of endothelial progenitors during postnatal vascular development.     

Transcranial direct current stimulation over somatosensory cortex decreases experimentally induced acute pain perception

OBJECTIVE: Multiple cortical areas including the primary somatosensory cortex are known to be involved in nociception. The aim of this study was to investigate the effect of transcranial direct current stimulation (tDCS) that modulates the cortical excitability painlessly and noninvasively, over somatosensory cortex on acute pain perception induced with a Tm:YAG laser. METHODS: Subjective pain rating scores and amplitude changes of the N1, N2, and P2 components of laser-evoked potentials of 10 healthy participants were analyzed before and after anodal, cathodal, and sham tDCS. RESULTS: Our results demonstrate that cathodal tDCS significantly diminished pain perception and the amplitude of the N2 component when the contralateral hand to the side of tDCS was laser-stimulated, whereas anodal and sham stimulation conditions had no significant effect. DISCUSSION: Our study highlights the antinociceptive effect of this technique and may contribute to the understanding of the mechanisms underlying pain relief. The pharmacologic prolongation of the excitability-diminishing after-effects would render the method applicable to different patient populations with chronic pain.     

Epidermal growth factor receptor (EGFR) high gene copy number and activating mutations in lung adenocarcinomas are not consistently accompanied by positivity for EGFR protein by standard immunohistochemistry

The purpose of this study was to investigate whether detectable protein biomarker overexpression is a prerequisite for the presence of increased gene copy number or activating mutations and responsiveness to the epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib in patients with lung adenocarcinomas. EGFR status was prospectively analyzed in tumor biopsy samples by three methods: protein expression (n = 117) by standardized immunohistochemistry (IHC), gene copy number (n = 97) by fluorescent in situ hybridization (FISH), and mutation analysis by sequencing (n = 126). Fifty-nine percent of the samples were positive by IHC, 40% were positive by FISH, and 13.5% contained activating kinase domain mutations. Thirty-four percent of the FISH-positive and 27% of the mutant samples were also IHC-negative. All EGFR mutant patients had major clinical responses (five complete response and five partial response) to gefitinib or erlotinib treatment, although three of these tumors were IHC-negative and four were FISH-negative. In a retrospective analysis of samples from nine patients with excellent therapeutic responses (three complete response, five partial response, one stable disease) to erlotinib or gefitinib, mutations were identified in eight cases, but IHC was negative in four of these tumors. These results indicate that molecular diagnostic methods appear to be most important for the identification of lung adenocarcinoma patients who may benefit from EGFR inhibitor treatments.     

Labeling of pancreatic islets with iron oxide nanoparticles for in vivo detection with magnetic resonance

In vitro labeling of pancreatic islets with iron nanoparticles enables their direct posttransplant visualization by magnetic resonance; however, there is still a discrepancy in the fate of iron nanoparticles. This study was performed to detail the labeling process, consequently to improve the labeling efficacy and to confirm safety for islet cells. The islets were visible on T2*-weighted magnetic resonance images as hypointense spots immediately after 1-hr cultivation. Although at this time already the sufficient superparamagnetic effect was achieved, most of the particles were deposed in islet macrophages and only later were they found in endosomes of endocrine islet cells. The iron content depended on length of culture period. The labeled islets showed an intact ultrastructure, responded normally to glucose stimulation in vitro, and were able to treat experimental diabetes. For purpose of subsequent magnetic resonance imaging, a 24-hr culture with ferucarbotran leads to sufficient labeling with no apparent adverse effect on beta cell morphology or function.     

Erlotinib directly inhibits HER2 kinase activation and downstream signaling events in intact cells lacking epidermal growth factor receptor expression

Erlotinib (Tarceva), is an orally available, reversible inhibitor of epidermal growth factor receptor (EGFR; HER1) that exhibits inhibitory activity on purified HER2 kinase at much higher concentrations. Despite the minimal activity on purified protein in vitro, in vivo studies show that erlotinib inhibits the growth of HER2-driven systems effectively. Several hypotheses have been put forward to explain this discrepancy. In particular, it has been suggested that erlotinib might indirectly suppress the activity of HER2 by blocking the ability of EGFR to transactivate it when the two receptors are part of a heterodimer complex. However, an alternative possibility that has not been adequately addressed is whether the direct inhibitory action of erlotinib on the HER2 kinase might account for the observed biological responses. To distinguish between a direct effect of erlotinib on HER2 kinase in intact cells or an indirect effect of erlotinib on HER2 activity that is mediated through EGFR, we generated cell lines that express either EGFR-H2 chimeric receptor or HER2 and HER3 receptors in an EGFR-negative background. We show that dose-dependent inhibition of HER2 was achieved at the receptor level, on downstream signaling molecules, and more importantly was also translated into inhibition of cell growth. Our findings imply that the inhibitory effect of erlotinib in HER2-expressing cells may in part be mediated through direct interaction with HER2 rather than indirectly through a process that requires the presence of EGFR.