Abrogation of Gap Junctional Communication in ES Cells Results in a Disruption of Primitive Endoderm Formation in Embryoid Bodies.

Gap junctional intercellular communication (GJIC) has been suggested to be involved in early embryonic development but the actual functional role remained elusive. Connexin (Cx) 43 and Cx45 are co-expressed in embryonic stem (ES) cells, form gap junctions and are considered to exhibit adhesive function and/or to contribute to the establishment of defined communication compartments. Here, we describe the generation of Cx43/Cx45-double deficient mouse ES cells to achieve almost complete breakdown of GJIC.

TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons.

Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces the number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43-knockdown neurons and decreased β2-transferrin levels in patient CSF Whole proteome quantification identified the upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons.

Specific Triazine Herbicides Induce Amyloid-β42 Production.

Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by secretases leads to extracellular release of amyloid-β (Aβ) peptides. Increased production of Aβ42 over Aβ40 and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark. Identifying products of the 'human chemical exposome' (HCE) able to induce Aβ42 production may be a key to understanding some of the initiating causes of AD and to generate non-genetic, chemically-induced AD animal models.

Functional Subclone Profiling for Prediction of Treatment-Induced Intratumor Population Shifts and Discovery of Rational Drug Combinations in Human Glioblastoma.

Purpose: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors.

Experimental Design: Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors.

Impedimetric real-time monitoring of neural pluripotent stem cell differentiation process on microelectrode arrays.

In today's neurodevelopment and -disease research, human neural stem/progenitor cell-derived networks represent the sole accessible in vitro model possessing a primary phenotype. However, cultivation and moreover, differentiation as well as maturation of human neural stem/progenitor cells are very complex and time-consuming processes. Therefore, techniques for the sensitive non-invasive, real-time monitoring of neuronal differentiation and maturation are highly demanded.

The earlier the better? Bevacizumab in the treatment of recurrent MGMT-non-methylated glioblastoma.

Purpose: The adequate second-line therapy of patients with glioblastoma (GBM) is a matter of ongoing debate. This particularly applies to patients with a non-methylated MGMT promotor who are known to have a poor response to alkylating chemotherapy. In some countries, antiangiogenic therapy with BEV is applied as second-line therapy, and in others nitrosourea therapy is second-line choice.

Modeling psychiatric disorders: from genomic findings to cellular phenotypes.

Major programs in psychiatric genetics have identified >150 risk loci for psychiatric disorders. These loci converge on a small number of functional pathways, which span conventional diagnostic criteria, suggesting a partly common biology underlying schizophrenia, autism and other psychiatric disorders. Nevertheless, the cellular phenotypes that capture the fundamental features of psychiatric disorders have not yet been determined.

Prognostic factors in recurrent glioblastoma patients treated with bevacizumab.

The value of bevacizumab (BEV) in recurrent glioblastoma is unclear. Imaging parameters and progression-free survival (PFS) are problematic endpoints. Few data exist on clinical factors influencing overall survival (OS) in unselected patients with recurrent glioblastoma exposed to BEV.

Polysialylation and lipopolysaccharide-induced shedding of E-selectin ligand-1 and neuropilin-2 by microglia and THP-1 macrophages.

Microglia are tissue macrophages and mediators of innate immune responses in the brain. The protein-modifying glycan polysialic acid (polySia) is implicated in modulating microglia activity. Cultured murine microglia maintain a pool of Golgi-confined polySia, which is depleted in response to lipopolysaccharide (LPS)-induced activation.

Phase I trial of dovitinib (TKI258) in recurrent glioblastoma.

Purpose: Dovitinib (TKI258) is an oral multi-tyrosine kinase inhibitor of FGFR, VEGFR, PDGFR β, and c-Kit. Since dovitinib is able to cross the blood-brain barrier and targets brain tumor-relevant pathways, we conducted a phase I trial to demonstrate its safety in recurrent glioblastoma (GBM).

Patients And Methods: Patients with first or second GBM recurrence started treatment with the maximal tolerated dose (MTD) previously established in systemic cancer patients (500 mg/d, 5 days on/2 days off).

Reelin Signaling in the Migration of Ventral Brain Stem and Spinal Cord Neurons.

The extracellular matrix protein Reelin is an important orchestrator of neuronal migration during the development of the central nervous system. While its role and mechanism of action have been extensively studied and reviewed in the formation of dorsal laminar brain structures like the cerebral cortex, hippocampus, and cerebellum, its functions during the neuronal migration events that result in the nuclear organization of the ventral central nervous system are less well understood. In an attempt to delineate an underlying pattern of Reelin action in the formation of neuronal cell clusters, this review highlights the role of Reelin signaling in the migration of neuronal populations that originate in the ventral brain stem and the spinal cord.

F-fluoroethyl-L-tyrosine positron emission tomography for the differential diagnosis of tumefactive multiple sclerosis versus glioma: A case report.

Large demyelinating inflammatory central nervous system (CNS) lesions may present with contrast enhancement on magnetic resonance imaging and may mimic CNS tumors such as glioma. In ambiguous cases, new diagnostic tools that may be helpful for distinguishing between demyelinating inflammatory and neoplastic CNS lesions are required. The current study presents the case of a patient with a large contrast-enhanced frontal brain lesion, who was initially diagnosed with tumefactive multiple sclerosis.

Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein.

Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic β-amyloid (Aβ) peptides produced by β- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP). β-secretase inhibitors reduce Aβ levels, but mechanism-based side effects arise because they also inhibit β-cleavage of non-amyloid substrates like Neuregulin.

Phosphorylation of the amyloid β-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity.

Aggregation and toxicity of the amyloid β-peptide (Aβ) are considered as critical events in the initiation and progression of Alzheimer's disease (AD). Recent evidence indicated that soluble oligomeric Aβ assemblies exert pronounced toxicity, rather than larger fibrillar aggregates that deposit in the forms of extracellular plaques. While some rare mutations in the Aβ sequence that cause early-onset AD promote the oligomerization, molecular mechanisms that induce the formation or stabilization of oligomers of the wild-type Aβ remain unclear.

Therapy of leptomeningeal metastasis in solid tumors.

Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors.

Nanog induces suppression of senescence through downregulation of p27KIP1 expression.

A comprehensive analysis of the molecular network of cellular factors establishing and maintaining pluripotency as well as self renewal of pluripotent stem cells is key for further progress in understanding basic stem cell biology. Nanog is necessary for the natural induction of pluripotency in early mammalian development but dispensable for both its maintenance and its artificial induction. To gain further insight into the molecular activity of Nanog, we analyzed the outcomes of Nanog gain-of-function in various cell models employing a recently developed biologically active recombinant cell-permeant protein, Nanog-TAT.

Erratum to: Gliomatosis cerebri: no evidence for a separate brain tumor entity.

Erratum to: Acta Neuropathol DOI 10.1007/s00401‑015‑1495‑z. The original version of this article contained errors in the alignment of several entries in Tables 4 and 5.

CD14 is a key organizer of microglial responses to CNS infection and injury.

Microglia, innate immune cells of the CNS, sense infection and damage through overlapping receptor sets. Toll-like receptor (TLR) 4 recognizes bacterial lipopolysaccharide (LPS) and multiple injury-associated factors. We show that its co-receptor CD14 serves three non-redundant functions in microglia.

Late Pseudoprogression in Glioblastoma: Diagnostic Value of Dynamic O-(2-[18F]fluoroethyl)-L-Tyrosine PET.

Purpose: Pseudoprogression (PsP) is characterized by therapy-associated but not tumor growth-associated increases of contrast-enhancing glioblastoma lesions on MRI. Although typically occurring during the first 3 months after radiochemotherapy, PsP may occur later in the course of the disease and may then be particularly difficult to distinguish from true tumor progression. We explored PET using O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET-PET) to approach the diagnostic dilemma.