Untersuchungen zu Expression und Funktion der miR-155 in Zellen der akuten Leukämie

Maligne Zellen zeigen häufig eine Dysregulation von microRNAs. In hämatologischen Neoplasien ist die miR-155 häufig dereguliert. Eine heterogene miR-155-Expression in unterschiedlichen Leukämien wurde nachgewiesen. Es zeigte sich eine Assoziation mit bestimmten Subtypen und mit prognostischen Markern, jedoch kein prognostischer Wert. Funktionelle Untersuchungen zeigten keinen Einfluss der miR-155 auf Proliferation und Zelltodprozesse, obwohl der PI3K/Akt-Signalweg enthemmt wird. Der Multikinaseinhibitor Sorafenib zeigt antileukämische Effekte und kann Einfluss auf die miR-155-Expression haben

During early stages of cancer, neutrophils initiate anti-tumor immune responses in tumor-draining lymph nodes

Tumor-draining lymph nodes (LNs) play a crucial role during cancer spread and in initiation of anti-cancer adaptive immunity. Neutrophils form a substantial population of cells in LNs with poorly understood functions. Here, we demonstrate that, during head and neck cancer (HNC) progression, tumor-associated neutrophils transmigrate to LNs and shape anti-tumor responses in a stage-dependent manner. In metastasis-free stages (N0), neutrophils develop an antigen-presenting phenotype (HLA-DR+CD80+CD86+ICAM1+PD-L1-) and stimulate T cells (CD27+Ki67highPD-1-). LN metastases release GM-CSF and via STAT3 trigger development of PD-L1+ immunosuppressive neutrophils, which repress T cell responses. The accumulation of neutrophils in T cell-rich zones of LNs in N0 constitutes a positive predictor for 5-year survival, while increased numbers of neutrophils in LNs of N1-3 stages predict poor prognosis in HNC. These results suggest a dual role of neutrophils as essential regulators of anti-cancer immunity in LNs and argue for approaches fostering immunostimulatory activity of these cells during cancer therapy

The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking

Ciliopathies are a genetically and phenotypically heterogeneous group of human developmental disorders whose root cause is the absence or dysfunction of primary cilia. Joubert syndrome is characterized by a distinctive hindbrain malformation variably associated with retinal dystrophy and cystic kidney disease. Mutations in CC2D2A are found in ∼10% of patients with Joubert syndrome. Here we describe the retinal phenotype of cc2d2a mutant zebrafish consisting of disorganized rod and cone photoreceptor outer segments resulting in abnormal visual function as measured by electroretinogram. Our analysis reveals trafficking defects in mutant photoreceptors affecting transmembrane outer segment proteins (opsins) and striking accumulation of vesicles, suggesting a role for Cc2d2a in vesicle trafficking and fusion. This is further supported by mislocalization of Rab8, a key regulator of opsin carrier vesicle trafficking, in cc2d2a mutant photoreceptors and by enhancement of the cc2d2a retinal and kidney phenotypes with partial knockdown of rab8. We demonstrate that Cc2d2a localizes to the connecting cilium in photoreceptors and to the transition zone in other ciliated cell types and that cilia are present in these cells in cc2d2a mutants, arguing against a primary function for Cc2d2a in ciliogenesis. Our data support a model where Cc2d2a, localized at the photoreceptor connecting cilium/transition zone, facilitates protein transport through a role in Rab8-dependent vesicle trafficking and fusion

Search for gravitational waves from low mass compact binary coalescence in LIGO's sixth science run and Virgo's science runs 2 and 3

We report on a search for gravitational waves from coalescing compact binaries using LIGO and Virgo observations between July 7, 2009, and October 20, 2010. We searched for signals from binaries with total mass between 2 and 25M⊙; this includes binary neutron stars, binary black holes, and binaries consisting of a black hole and neutron star. The detectors were sensitive to systems up to 40 Mpc distant for binary neutron stars, and further for higher mass systems. No gravitational-wave signals were detected. We report upper limits on the rate of compact binary coalescence as a function of total mass, including the results from previous LIGO and Virgo observations. The cumulative 90% confidence rate upper limits of the binary coalescence of binary neutron star, neutron star-black hole, and binary black hole systems are 1.3×10−4, 3.1×10−5, and 6.4×10−6  Mpc−3 yr−1, respectively. These upper limits are up to a factor 1.4 lower than previously derived limits. We also report on results from a blind injection challenge. © 2012 The American Physical Societ

Upper limits on a stochastic gravitational-wave background using LIGO and Virgo interferometers at 600-1000 Hz

A stochastic background of gravitational waves is expected to arise from a superposition of many incoherent sources of gravitational waves, of either cosmological or astrophysical origin. This background is a target for the current generation of ground-based detectors. In this article we present the first joint search for a stochastic background using data from the LIGO and Virgo interferometers. In a frequency band of 600–1000 Hz, we obtained a 95% upper limit on the amplitude of ΩGW(f)=Ω3(f/900  Hz)3, of Ω3<0.32, assuming a value of the Hubble parameter of h100=0.71. These new limits are a factor of seven better than the previous best in this frequency band. © 2012 The American Physical Societ

All-sky search for gravitational-wave bursts in the second joint LIGO-Virgo run

We present results from a search for gravitational-wave bursts in the data collected by the LIGO and Virgo detectors between July 7, 2009 and October 20, 2010: data are analyzed when at least two of the three LIGO-Virgo detectors are in coincident operation, with a total observation time of 207 days. The analysis searches for transients of duration ≲1  s over the frequency band 64–5000 Hz, without other assumptions on the signal waveform, polarization, direction or occurrence time. All identified events are consistent with the expected accidental background. We set frequentist upper limits on the rate of gravitational-wave bursts by combining this search with the previous LIGO-Virgo search on the data collected between November 2005 and October 2007. The upper limit on the rate of strong gravitational-wave bursts at the Earth is 1.3 events per year at 90% confidence. We also present upper limits on source rate density per year and Mpc3 for sample populations of standard-candle sources. As in the previous joint run, typical sensitivities of the search in terms of the root-sum-squared strain amplitude for these waveforms lie in the range ∼5×10−22  Hz−1/2 to ∼1×10−20  Hz−1/2. The combination of the two joint runs entails the most sensitive all-sky search for generic gravitational-wave bursts and synthesizes the results achieved by the initial generation of interferometric detectors. © 2012 The American Physical Societ

Search for gravitational waves from compact binary coalescence in LIGO and Virgo data from S5 and VSR1

We report the results of the first search for gravitational waves from compact binary coalescence using data from the Laser Interferometer Gravitational-Wave Observatory and Virgo detectors. Five months of data were collected during the Laser Interferometer Gravitational-Wave Observatory’s S5 and Virgo’s VSR1 science runs. The search focused on signals from binary mergers with a total mass between 2 and 35M⊙. No gravitational waves are identified. The cumulative 90%-confidence upper limits on the rate of compact binary coalescence are calculated for nonspinning binary neutron stars, black hole-neutron star systems, and binary black holes to be 8.7×10−3  yr−1 L10−1, 2.2×10−3  yr−1 L10−1, and 4.4×10−4  yr−1 L10−1, respectively, where L10 is 1010 times the blue solar luminosity. These upper limits are compared with astrophysical expectations. © 2010 The American Physical Societ

Search for gravitational waves from intermediate mass binary black holes

We present the results of a weakly modeled burst search for gravitational waves from mergers of nonspinning intermediate mass black holes in the total mass range 100–450  M⊙ and with the component mass ratios between 1∶1 and 4∶1. The search was conducted on data collected by the LIGO and Virgo detectors between November of 2005 and October of 2007. No plausible signals were observed by the search which constrains the astrophysical rates of the intermediate mass black holes mergers as a function of the component masses. In the most efficiently detected bin centered on 88+88  M⊙, for nonspinning sources, the rate density upper limit is 0.13 per Mpc3 per Myr at the 90% confidence level. © 2012 The American Physical Societ

All-sky search for periodic gravitational waves in the full S5 LIGO data

We report on an all-sky search for periodic gravitational waves in the frequency band 50–800 Hz and with the frequency time derivative in the range of 0 through −6×10−9  Hz/s. Such a signal could be produced by a nearby spinning and slightly nonaxisymmetric isolated neutron star in our Galaxy. After recent improvements in the search program that yielded a 10× increase in computational efficiency, we have searched in two years of data collected during LIGO’s fifth science run and have obtained the most sensitive all-sky upper limits on gravitational-wave strain to date. Near 150 Hz our upper limit on worst-case linearly polarized strain amplitude h0 is 1×10−24, while at the high end of our frequency range we achieve a worst-case upper limit of 3.8×10−24 for all polarizations and sky locations. These results constitute a factor of 2 improvement upon previously published data. A new detection pipeline utilizing a loosely coherent algorithm was able to follow up weaker outliers, increasing the volume of space where signals can be detected by a factor of 10, but has not revealed any gravitational-wave signals. The pipeline has been tested for robustness with respect to deviations from the model of an isolated neutron star, such as caused by a low-mass or long-period binary companion. © 2012 The American Physical Societ