Tumor cell-selective apoptosis induction through targeting of KV10.1 via bifunctional TRAIL antibody

<p>Abstract</p> <p>Background</p> <p>The search for strategies to target ion channels for therapeutic applications has become of increasing interest. Especially, the potassium channel K_V10.1 (Ether-á-go-go) is attractive as target since this surface protein is virtually not detected in normal tissue outside the central nervous system, but is expressed in approximately 70% of tumors from different origins.</p> <p>Methods</p> <p>We designed a single-chain antibody against an extracellular region of K_V10.1 (scFv62) and fused it to the human soluble TRAIL. The K_V10.1-specific scFv62 antibody -TRAIL fusion protein was expressed in CHO-K1 cells, purified by chromatography and tested for biological activity.</p> <p>Results</p> <p>Prostate cancer cells, either positive or negative for K_V10.1 were treated with the purified construct. After sensitization with cytotoxic drugs, scFv62-TRAIL induced apoptosis only in K_V10.1-positive cancer cells, but not in non-tumor cells, nor in tumor cells lacking K_V10.1 expression. In co-cultures with K_V10.1-positive cancer cells the fusion protein also induced apoptosis in bystander K_V10.1-negative cancer cells, while normal prostate epithelial cells were not affected when present as bystander.</p> <p>Conclusions</p> <p>K_V10.1 represents a novel therapeutic target for cancer. We could design a strategy that selectively kills tumor cells based on a K_V10.1-specific antibody.</p

A Giant Planet Around a Metal-poor Star of Extragalactic Origin

Stars in their late stage of evolution, such as Horizontal Branch stars, are still largely unexplored for planets. We report the detection of a planetary companion around HIP 13044, a very metal-poor star on the red Horizontal Branch, based on radial velocity observations with a high-resolution spectrograph at the 2.2-m MPG/ESO telescope. The star's periodic radial velocity variation of P=16.2 days caused by the planet can be distinguished from the periods of the stellar activity indicators. The minimum mass of the planet is 1.25 Jupiter masses and its orbital semi-major axis 0.116 AU. Because HIP 13044 belongs to a group of stars that have been accreted from a disrupted satellite galaxy of the Milky Way, the planet most likely has an extragalactic origin.Comment: 32 pages, 9 Figure

Potassium channels as tumour markers

AbstractAn increasing number of ion channels are being found to be causally involved in diseases, giving rise to the new field of “channelopathies”. Cancer is no exception, and several ion channels have been linked to tumour progression. Among them is the potassium channel EAG (Ether-a-go-go). Over 75% of tumours have been tested positive using a monoclonal antibody specific for EAG, while inhibition of this channel decreased the proliferation of EAG expressing cells. The inhibition of EAG is accomplished using RNA interference, functional anti-EAG1 antibodies, or (unspecific) EAG channel blockers. Fluorescently labelled recombinant Fab fragments recognizing EAG allow the distribution of EAG to be visualized in an in vivo mouse tumour model

The visitor from an ancient galaxy: A planetary companion around an old, metal-poor red horizontal branch star

We report the detection of a planetary companion around HIP 13044, a metal-poor red horizontal branch star belonging to a stellar halo stream that results from the disruption of an ancient Milky Way satellite galaxy. The detection is based on radial velocity observations with FEROS at the 2.2-m MPG/ESO telescope. The periodic radial velocity variation of P=16.2 days can be distinguished from the periods of the stellar activity indicators. We computed a minimum planetary mass of 1.25 Jupiter masses and an orbital semimajor axis of 0.116 AU for the planet. This discovery is unique in three aspects: First, it is the first planet detection around a star with a metallicity much lower than few percent of the solar value; second, the planet host star resides in a stellar evolutionary stage that is still unexplored in the exoplanet surveys; third, the planetary system HIP 13044 most likely has an extragalactic origin in a disrupted former satellite of the Milky Way.Comment: 5 pages, 2 figures, 2 tables, submitted to the Proceedings of the 276th IAU Symposium "The Astrophysics of Planetary Systems

A Planetary Companion around a Metal-Poor Star with Extragalactic Origin

We report the detection of a planetary companion around HIP 13044, a metal-poor star on the red Horizontal Branch. The detection is based on radial velocity observations with FEROS, a high-resolution spectrograph at the 2.2-m MPG/ESO telescope, located at ESO La Silla observatory in Chile. The periodic radial velocity variation of P = 16.2 days can be distinguished from the periods of the stellar activity indicators. We computed a minimum planetary mass of 1.25 MJup and an orbital semi-major axis of 0.116 AU for the planet. This discovery is unique in three aspects: First, it is the first planet detection around a star with a metallicity much lower than few percent of the solar value; second, the planet host star resides in a stellar evolutionary stage that is still unexplored in the exoplanet surveys; third, the star HIP 13044 belongs to one of the most significant stellar halo streams in the solar neighborhood, implying an extragalactic origin of the planetary system HIP 13044 in a disrupted former satellite of the Milky Way.Comment: Part of PlanetsbeyondMS/2010 proceedings http://arxiv.org/html/1011.660

A new role for interferon gamma in neural stem/precursor cell dysregulation

BACKGROUND: The identification of factors that compromise neurogenesis is aimed at improving stem cell-based approaches in the field of regenerative medicine. Interferon gamma (IFNγ) is a main pro-inflammatory cytokine and up-regulated during several neurological diseases. IFNγ is generally thought to beneficially enhance neurogenesis from fetal or adult neural stem/precursor cells (NSPCs). RESULTS: We now provide direct evidence to the contrary that IFNγ induces a dysfunctional stage in a substantial portion of NSPC-derived progeny in vitro characterized by simultaneous expression of glial fibrillary acid protein (GFAP) and neuronal markers, an abnormal gene expression and a functional phenotype neither typical for neurons nor for mature astrocytes. Dysfunctional development of NSPCs under the influence of IFNγ was finally demonstrated by applying the microelectrode array technology. IFNγ exposure of NSPCs during an initial 7-day proliferation period prevented the subsequent adequate differentiation and formation of functional neuronal networks. CONCLUSIONS: Our results show that immunocytochemical analyses of NSPC-derived progeny are not necessarily indicating the correct cellular phenotype specifically under inflammatory conditions and that simultaneous expression of neuronal and glial markers rather point to cellular dysregulation. We hypothesize that inhibiting the impact of IFNγ on NSPCs during neurological diseases might contribute to effective neurogenesis and regeneration

Quantitative analysis of processive RNA degradation by the archaeal RNA exosome

RNA exosomes are large multisubunit assemblies involved in controlled RNA processing. The archaeal exosome possesses a heterohexameric processing chamber with three RNase-PH-like active sites, capped by Rrp4- or Csl4-type subunits containing RNA-binding domains. RNA degradation by RNA exosomes has not been studied in a quantitative manner because of the complex kinetics involved, and exosome features contributing to efficient RNA degradation remain unclear. Here we derive a quantitative kinetic model for degradation of a model substrate by the archaeal exosome. Markov Chain Monte Carlo methods for parameter estimation allow for the comparison of reaction kinetics between different exosome variants and substrates. We show that long substrates are degraded in a processive and short RNA in a more distributive manner and that the cap proteins influence degradation speed. Our results, supported by small angle X-ray scattering, suggest that the Rrp4-type cap efficiently recruits RNA but prevents fast RNA degradation of longer RNAs by molecular friction, likely by RNA contacts to its unique KH-domain. We also show that formation of the RNase-PH like ring with entrapped RNA is not required for high catalytic efficiency, suggesting that the exosome chamber evolved for controlled processivity, rather than for catalytic chemistry in RNA decay

International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes

A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially-driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a roadmap towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.JRC.I.5-Systems Toxicolog

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

First Observation of Self-Amplified Spontaneous Emission in a Free-Electron Laser at 109 nm Wavelength

We present the first observation of Self-Amplified Spontaneous Emission (SASE) in a free-electron laser (FEL) in the Vacuum Ultraviolet regime at 109 nm wavelength (11 eV). The observed free-electron laser gain (approx. 3000) and the radiation characteristics, such as dependency on bunch charge, angular distribution, spectral width and intensity fluctuations all corroborate the existing models for SASE FELs.Comment: 6 pages including 6 figures; e-mail: [email protected]