The rockefeller university

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

Tenofovir alafenamide (formerly GS-7340) is a new oral prodrug of tenofovir, a nucleotide analogue that inhibits HIV-1 reverse transcription. Unlike the currently marketed tenofovir prodrug, tenofovir disoproxil fumarate, tenofovir alafenamide is stable in plasma and then rapidly converted into tenofovir once inside cells. The pharmacokinetics, safety and antiviral activity of 40 or 120 mg of tenofovir alafenamide compared with 300 mg of tenofovir disoproxil fumarate when administered as monotherapy once daily for 14 days in HIV-1-infected, treatment-naive subjects was studied. Administration of 40 mg of tenofovir alafenamide for 14 days resulted in lower tenofovir C-max (13 versus 207 ng/mL) and lower systemic exposures (AUC(0t), 383 versus 1810 ngh/mL) compared with subjects who received tenofovir disoproxil fumarate. There were higher intracellular tenofovir concentrations within peripheral blood mononuclear cells with both 40 mg of tenofovir alafenamide (8.2 M) and 120 mg of tenofovir alafenamide (16.9 M) compared with 300 mg of tenofovir disoproxil fumarate (0.9 M). The most commonly observed adverse events were headache, nausea and flatulence, which occurred similarly across the three groups. After 14 days, the mean changes in HIV-1 RNA were 0.94 log(10)copies/mL for the tenofovir disoproxil fumarate group, 1.57 log(10) copies/mL for the 40 mg of tenofovir alafenamide group and 1.71 log(10) copies/mL for the 120 mg of tenofovir alafenamide group. The mean first-phase HIV-1 RNA decay slopes were 0.36, 0.63 and 0.64 for the tenofovir disoproxil fumarate group, the 40 mg of tenofovir alafenamide group and the 120 mg of tenofovir alafenamide group, respectively. No resistance mutations to either tenofovir alafenamide or tenofovir disoproxil fumarate were detected. Tenofovir alafenamide, a new once-daily oral prodrug of tenofovir, showed more potent anti-HIV-1 activity and higher intracellular tenofovir levels compared with tenofovir disoproxil fumarate, while maintaining lower plasma tenofovir exposure at 40 mg with good tolerability over 14 days of monotherapy.

Cell migration and invasion require increased plasma membrane dynamics and ability to navigate through dense stroma, thereby exposing plasma membrane to tremendous physical stress. Yet, it is largely unknown how metastatic cancer cells acquire an ability to cope with such stress. Here we show that S100A11, a calcium-binding protein upregulated in a variety of metastatic cancers, is essential for efficient plasma membrane repair and survival of highly motile cancer cells. Plasma membrane injury-induced entry of calcium into the cell triggers recruitment of S100A11 and Annexin A2 to the site of injury. We show that S100A11 in a complex with Annexin A2 helps reseal the plasma membrane by facilitating polymerization of cortical F-actin and excision of the damaged part of the plasma membrane. These data reveal plasma membrane repair in general and S100A11 and Annexin A2 in particular as new targets for the therapy of metastatic cancers.

Introduction: Psoriasis is a chronic inflammatory skin disorder determined by the activation of several immune cells and resident tissue cells. Various cytokines mediate inflammatory signals, including IL-23, which is an important factor involved in the differentiation of T helper (Th17) cells. Areas covered: Increasing evidence suggests that IL-23 is a central cytokine to the pathogenesis of psoriasis. An overview on both experimental and human data will be reported in order to support the hypothesis of a key pathogenic role of IL-23/Th17 axis. Expert opinion: Targeting IL-23 might be a more selective, valid and effective therapeutic approach, which, potentially, may show important advantages in terms of long-term efficacy and safety in the treatment of psoriasis.

Preeclampsia (PE) is considered to be a potentially fatal complication during pregnancy. However, no effective laboratory assessment has been developed to enable early diagnosis and monitoring of PE. The present study aimed to identify differentially expressed transthyretin (TTR) during severe PE and evaluate TTR as a possible biomarker of this disease. TTR levels were determined in the different gestational weeks of normal pregnancy (before 20 weeks, n=41; after 20 weeks, n=39) using enzyme-linked immunosorbent assay (ELISA). TTR concentrations in pregnant females with severe PE (n=43) were compared with those in healthy matched control subjects (n=37) using western blot analysis and ELISA. The median TTR concentration during severe PE in each month of gestation was significantly lower than the concentrations recorded during normal pregnancy. TTR levels in females with severe PE were significantly downregulated compared with the control subjects (P<0.001; area under the curve, 0.834-0.967). Thus, TTR may be used as a potential biomarker of PE.

The firing activity of intracellularly stimulated neurons in cortical slices has been demonstrated to be profoundly affected by the temporal structure of the injected current (Mainen & Sejnowski, 1995). This suggests that the timing features of the neural response may be controlled as much by its own biophysical characteristics as by how a neuron is wired within a circuit. Modeling studies have shown that the interplay between internal noise and the fluctuations of the driving input controls the reliability and the precision of neuronal spiking (Cecchi et al., 2000; Tiesinga, 2002; Fellous, Rudolph, Destexhe, & Sejnowski, 2003). In order to investigate this interplay, we focus on the stochastic leaky integrate-and-fire neuron and identify the Holder exponent H of the integrated input as the key mathematical property dictating the regime of firing of a single-unit neuron. We have recently provided numerical evidence (Taillefumier & Magnasco, 2013) for the existence of a phase transition when becomes less than the statistical Holder exponent associated with internal gaussian white noise (H=1/2). Here we describe the theoretical and numerical framework devised for the study of a neuron that is periodically driven by frozen noisy inputs with exponent H > 0. In doing so, we account for the existence of a transition between two regimes of firing when H=1/2, and we show that spiking times have a continuous density when the Holder exponent satisfies H > 1/2. The transition at H=1/2 formally separates rate codes, for which the neural firing probability varies smoothly, from temporal codes, for which the neuron fires at sharply defined times regardless of the intensity of internal noise.

Phenotype-based screening of bacterial metagenomic libraries provides an avenue for the discovery of novel genes, enzymes, and metabolites that have a variety of potential clinical and industrial uses. Here, we report the identification of a functionally diverse collection of antibacterially active enzymes from the phenotypic screening of 700000 cosmid clones prepared from Arizona soil DNA and hosted in Ralstonia metallidurans. Environmental DNA clones surrounded by zones of growth inhibition in a bacterial overlay assay were found, through bioinformatics and functional analyses, to encode enzymes with predicted peptidase, lipase, and glycolytic activities conferring antibiosis. The antibacterial activities observed in our R.metallidurans-based assay could not be replicated with the same clones in screens using Escherichia coli as a heterologous host, suggesting that the large-scale screening of metagenomic libraries for antibiosis using phylogenetically diverse hosts should be a productive strategy for identifying enzymes with functionally diverse antibacterial activities.

Measurements of the differential cross sections for the production of exactly four jets in proton-proton collisions are presented as a function of the transverse momentum p(T) and pseudorapidity eta, together with the correlations in azimuthal angle and the p(T) balance among the jets. The data sample was collected in 2010 at a center-of-mass energy of 7 TeV with the CMS detector at the LHC, with an integrated luminosity of 36 pb(-1). The cross section for exactly four jets, with two hard jets of p(T) > 50 GeV each, together with two jets of p(T) > 20 GeV each, within vertical bar eta vertical bar < 4.7 is measured to be sigma = 330 +/- 5(stat.) +/- 45(syst.) nb. It is found that fixed-order matrix element calculations including parton showers describe the measured differential cross sections in some regions of phase space only, and that adding contributions from double parton scattering brings the Monte Carlo predictions closer to the data.

Lysins are bacteriophage-derived enzymes that degrade bacterial peptidoglycans. Lysin CF-301 is being developed to treat Staphylococcus aureus because of its potent, specific, and rapid bacteriolytic effects. It also demonstrates activity on drug-resistant strains, has a low resistance profile, eradicates biofilms, and acts synergistically with antibiotics. CF-301 was bacteriolytic against 250 S. aureus strains tested including 120 methicillin-resistant S. aureus (MRSA) isolates. In time-kill studies with 62 strains, CF-301 reduced S. aureus by 3-log(10) within 30 minutes compared to 6-12 hours required by antibiotics. In bacteremia, CF-301 increased survival by reducing blood MRSA 100-fold within 1 hour. Combinations of CF-301 with vancomycin or daptomycin synergized in vitro and increased survival significantly in staphylococcal-induced bacteremia compared to treatment with antibiotics alone (P < .0001). Superiority of CF-301 combinations with antibiotics was confirmed in 26 independent bacteremia studies. Combinations including CF-301 and antibiotics represent an attractive alternative to antibiotic monotherapies currently used to treat S. aureus bacteremia.