Loss-of-function analysis of EphA receptors in retinotectal mapping

Peer reviewedPublisher PD

Lhx6 Delineates a Pathway Mediating Innate Reproductive Behaviors from the Amygdala to the Hypothalamus

In mammals, innate reproductive and defensive behaviors are mediated by anatomically segregated connections between the amygdala and hypothalamus. This anatomic segregation poses the problem of how the brain integrates activity in these circuits when faced with conflicting stimuli eliciting such mutually exclusive behaviors. Using genetically encoded and conventional axonal tracers, we have found that the transcription factor Lhx6 delineates the reproductive branch of this pathway. Other Lhx proteins mark neurons in amygdalar nuclei implicated in defense. We have traced parallel projections from the posterior medial amygdala, activated by reproductive or defensive olfactory stimuli, respectively, to a point of convergence in the ventromedial hypothalamus. The opposite neurotransmitter phenotypes of these convergent projections suggest a “gate control” mechanism for the inhibition of reproductive behaviors by threatening stimuli. Our data therefore identify a potential neural substrate for integrating the influences of conflicting behavioral cues and a transcription factor family that may contribute to the development of this substrate

VEGF Trap In Combination With Radiotherapy Improves Tumor Control In U87 Glioblastoma

Purpose To determine the effect of vascular endothelial growth factor VEGF Trap (Regeneron Pharmaceuticals, Tarrytown, NY), a humanized soluble vascular endothelial growth factor (VEGF) receptor protein, and radiation (RT) on tumor growth in U87 glioblastoma xenografts in nude mice. Methods and Materials U87 cell suspensions were implanted subcutaneously into hind limbs of nude mice. VEGF Trap (2.5–25 mg/kg) was administered every 3 days for 3 weeks alone or in combination with a single dose of 10 Gy or fractionated RT (3 x 5 Gy). In addition, three scheduling protocols for VEGF Trap plus fractionated RT were examined. Results Improved tumor control was seen when RT (either single dose or fractionated doses) was combined with the lowest dose of VEGF Trap (2.5 mg/kg). Scheduling did not significantly affect the efficacy of combined therapy. Although high-dose VEGF Trap (10 mg/kg or 25 mg/kg) significantly reduced tumor growth over that of RT alone, there was no additional benefit to combining high-dose VEGF Trap with RT. Conclusions Vascular endothelial growth factor Trap plus radiation is clearly better than radiation alone in a U87 subcutaneous xenograft model. Although high doses of VEGF Trap alone are highly efficacious, it is unclear whether such high doses can be used clinically without incurring normal tissue toxicities. Thus, information on lower doses of VEGF Trap and ionizing radiation is of clinical relevance. Int. J. Radiation Oncol. Biol. Physics, Volume 67, Issue 5, pages 1526-1537, 2007

Sarilumab for the treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN)

OBJECTIVES: The ALIGN study (NCT01061723) evaluated the efficacy and safety of sarilumab, the first fully human monoclonal antibody against interleukin-6 receptor-alpha (IL-6Ralpha), in patients with ankylosing spondylitis (AS). METHODS: Patients with active AS despite conventional treatment were randomised to placebo, or one of five subcutaneous dose regimens of sarilumab (100, 150 or 200 mg every other week, or 100 or 150 mg every week), for 12 weeks. The primary efficacy end point was the percentage of patients achieving the Axial SpondyloArthritis international Society (ASAS) 20 response criteria at week 12. Secondary endpoints included ASAS40 response, ASAS partial remission, AS Disease Activity Score, high-sensitivity C-reactive protein (hs-CRP) value, and safety. RESULTS: Baseline demographic and disease characteristics of the 301 patients enrolled were similar across treatment groups. At week 12, there was no statistically significant difference in ASAS20 response rate between placebo (ASAS20 = 24.0%) and any sarilumab dose group. A significantly greater reduction in hs-CRP value was achieved with the higher sarilumab doses versus placebo. No other statistically significant differences were evident for secondary efficacy endpoints.The most common treatment-emergent adverse events reported for sarilumab included infections (non-serious), neutropenia, and increase in alanine aminotransferase. No cases of tuberculosis, opportunistic, or fungal infections, or bowel perforations were reported. Seven patients experienced a treatment-emergent serious adverse event (all in sarilumab treatment groups). No deaths occurred. CONCLUSIONS: The ALIGN study shows that IL-6Ralpha blockade with sarilumab was not an effective treatment for AS. Sarilumab was generally well tolerated with a manageable safety profile

Selective inhibition of kindling development by intraventricular administration of TrkB receptor body.

Recent work has shown that neurotrophin gene expression is increased after seizures evoked in the kindling model of epilepsy, but whether neurotrophins regulate kindling development is as yet unclear. In this study, we attempted to block selectively the activation of distinct neurotrophin receptors throughout kindling development in the rat via chronic intracerebroventricular administration of trk receptor bodies. The efficacy and selectivity of the trk receptor bodies were established by inhibition of neurotrophin-induced trk receptor phosphorylation in pheochromocytoma (PC12) cells and primary cultures of cortical neurons. The intracerebroventricular infusion of trkB receptor body (trkB-Fc) inhibited development of kindling in comparison with that seen with saline or human IgG controls, trkA-Fc, or trkC-Fc. These results imply that activation of trkB receptors contributes to the development of kindling, a form of activitydependent behavioral plasticity in the adult mammalian brain

Dose-dependent effects of Allopurinol on human foreskin fibroblast cell and human umbilical vein endothelial cell under hypoxia

Allopurinol, an inhibitor of xanthine oxidase, has been used in clinical trials of patients with cardiovascular and chronic kidney disease. These are two pathologies with extensive links to hypoxia and activation of the transcription factor hypoxia inducible factor (HIF) family. Here we analysed the effects of allopurinol treatment in two different cellular models, and their response to hypoxia. We explored the dose-dependent effect of allopurinol on Human Foreskin Fibroblasts (HFF) and Human Umbilical Vein Endothelial Cells (HUVEC) under hypoxia and normoxia. Under normoxia and hypoxia, high dose allopurinol reduced the accumulation of HIF-1α protein in HFF and HUVEC cells. Allopurinol had only marginal effects on HIF-1α mRNA level in both cellular systems. Interestingly, allopurinol effects over the HIF system were independent of prolyl-hydroxylase activity. Finally, allopurinol treatment reduced angiogenesis traits in HUVEC cells in an in vitro model. Taken together these results indicate that high doses of allopurinol inhibits the HIF system and pro-angiogenic traits in cells

Alternatively activated macrophage-derived RELM-α is a negative regulator of type 2 inflammation in the lung

Differentiation and recruitment of alternatively activated macrophages (AAMacs) are hallmarks of several inflammatory conditions associated with infection, allergy, diabetes, and cancer. AAMacs are defined by the expression of Arginase 1, chitinase-like molecules, and resistin-like molecule (RELM) α/FIZZ1; however, the influence of these molecules on the development, progression, or resolution of inflammatory diseases is unknown. We describe the generation of RELM-α–deficient (Retnla−/−) mice and use a model of T helper type 2 (Th2) cytokine-dependent lung inflammation to identify an immunoregulatory role for RELM-α. After challenge with Schistosoma mansoni (Sm) eggs, Retnla−/− mice developed exacerbated lung inflammation compared with their wild-type counterparts, characterized by excessive pulmonary vascularization, increased size of egg-induced granulomas, and elevated fibrosis. Associated with increased disease severity, Sm egg–challenged Retnla−/− mice exhibited elevated expression of pathogen-specific CD4+ T cell–derived Th2 cytokines. Consistent with immunoregulatory properties, recombinant RELM-α could bind to macrophages and effector CD4+ Th2 cells and inhibited Th2 cytokine production in a Bruton's tyrosine kinase–dependent manner. Additionally, Retnla−/− AAMacs promoted exaggerated antigen-specific Th2 cell differentiation. Collectively, these data identify a previously unrecognized role for AAMac-derived RELM-α in limiting the pathogenesis of Th2 cytokine-mediated pulmonary inflammation, in part through the regulation of CD4+ T cell responses