Purpose: The effects of pan–histone deacetylase (HDAC) inhibitors on cancer cells have shown that HDACs are involved in fundamental
tumor biological processes such as cell cycle control, ...differentiation, and apoptosis. However, because of the unselective
nature of these compounds, little is known about the contribution of individual HDAC family members to tumorigenesis and progression.
The purpose of this study was to evaluate the role of individual HDACs in neuroblastoma tumorigenesis.
Experimental Design: We have investigated the mRNA expression of all HDAC1-11 family members in a large cohort of primary neuroblastoma samples
covering the full spectrum of the disease. HDACs associated with disease stage and survival were subsequently functionally
evaluated in cell culture models.
Results: Only HDAC8 expression was significantly correlated with advanced disease and metastasis and down-regulated in stage 4S neuroblastoma
associated with spontaneous regression. High HDAC8 expression was associated with poor prognostic markers and poor overall and event-free survival. The knockdown of HDAC8 resulted
in the inhibition of proliferation, reduced clonogenic growth, cell cycle arrest, and differentiation in cultured neuroblastoma
cells. The treatment of neuroblastoma cell lines as well as short-term-culture neuroblastoma cells with an HDAC8-selective
small-molecule inhibitor inhibited cell proliferation and clone formation, induced differentiation, and thus reproduced the
HDAC8 knockdown phenotype. Global histone 4 acetylation was not affected by HDAC8 knockdown or by selective inhibitor treatment.
Conclusions: Our data point toward an important role of HDAC8 in neuroblastoma pathogenesis and identify this HDAC family member as a
specific drug target for the differentiation therapy of neuroblastoma.
Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone ...deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived- amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome.
•Approaches for CO2 leakage detection, attribution and quantification monitoring exist.•Many approaches cover multiple monitoring tasks simultaneously.•Sonars and chemical sensors on ships or AUVs ...can cover large areas.•Newer, more specific technologies can detect, verify and quantify smaller, localised leaks.
Environmental monitoring of offshore Carbon Capture and Storage (CCS) complexes requires robust methodologies and cost-effective tools to detect, attribute and quantify CO2 leakage in the unlikely event it occurs from a sub-seafloor reservoir. Various approaches can be utilised for environmental CCS monitoring, but their capabilities are often undemonstrated and more detailed monitoring strategies need to be developed. We tested and compared different approaches in an offshore setting using a CO2 release experiment conducted at 120 m water depth in the Central North Sea. Tests were carried out over a range of CO2 injection rates (6 - 143 kg d−1) comparable to emission rates observed from abandoned wells. Here, we discuss the benefits and challenges of the tested approaches and compare their relative cost, temporal and spatial resolution, technology readiness level and sensitivity to leakage. The individual approaches demonstrate a high level of sensitivity and certainty and cover a wide range of operational requirements. Additionally, we refer to a set of generic requirements for site-specific baseline surveys that will aid in the interpretation of the results. Critically, we show that the capability of most techniques to detect and quantify leakage exceeds the currently existing legal requirements.
Cold-water coral communities form complex benthic ecosystems in a distinct part of the water column. The exact processes supporting reef growth and changes with time are still partly unsolved. Recent ...studies have suggested a tidally driven hydraulic control of flow over topographic features as a driver for local downwelling at cold-water coral sites. This mechanism forms a link between surface and coral growth depths and is a driver of resuspension of the bottom material. Only few studies have concentrated on how these processes vary with the health status and structure of the cold-water coral occurrences. In this study, we explore the processes over tidal cycles by analysing in situ stratification, hydrography and velocity data which we then combine with local topography from seven Lophelia pertusa dominated eastern Atlantic cold-water coral sites. The “quality” of coral sites varies from thriving reefs to declining and dead coral sites. We show that living and healthy corals are concentrated at sites, where local hydrodynamics create overturning and mixing which support food supply for filter-feeding corals.
Cold seep ecosystems can support enormous biomasses of free-living and symbiotic chemoautotrophic organisms that get their energy from the oxidation of methane or sulfide. Most of this biomass ...derives from animals that are associated with bacterial symbionts, which are able to metabolize the chemical resources provided by the seeping fluids. Often these systems also harbor dense accumulations of non-symbiotic megafauna, which can be relevant in exporting chemosynthetically fixed carbon from seeps to the surrounding deep sea. Here we investigated the carbon sources of lithodid crabs (Paralomis sp.) feeding on thiotrophic bacterial mats at an active mud volcano at the Costa Rica subduction zone. To evaluate the dietary carbon source of the crabs, we compared the microbial community in stomach contents with surface sediments covered by microbial mats. The stomach content analyses revealed a dominance of epsilonproteobacterial 16S rRNA gene sequences related to the free-living and epibiotic sulfur oxidiser Sulfurovum sp. We also found Sulfurovum sp. as well as members of the genera Arcobacter and Sulfurimonas in mat-covered surface sediments where Epsilonproteobacteria were highly abundant constituting 10% of total cells. Furthermore, we detected substantial amounts of bacterial fatty acids such as i-C15∶0 and C17∶1ω6c with stable carbon isotope compositions as low as -53‰ in the stomach and muscle tissue. These results indicate that the white microbial mats at Mound 12 are comprised of Epsilonproteobacteria and that microbial mat-derived carbon provides an important contribution to the crab's nutrition. In addition, our lipid analyses also suggest that the crabs feed on other (13)C-depleted organic matter sources, possibly symbiotic megafauna as well as on photosynthetic carbon sources such as sedimentary detritus.
Bubble transport of methane from shallow seep sites in the Black Sea west of the Crimea Peninsula between 70 and 112 m water depth has been studied by extrapolation of results gained through ...different hydroacoustic methods and direct sampling. Ship‐based hydroacoustic echo sounders can locate bubble releasing seep sites very precisely and facilitate their correlation with geological or other features at the seafloor. Here, the backscatter strength of a multibeam system was integrated with single‐beam data to estimate the amount of seeps/m2 for different backscatter intensities, resulting in 2709 vents in total. Direct flux measurements by submersible revealed methane fluxes from individual vents of 0.32–0.85 l/min or 14.5–37.8 mmol/min at ambient pressure and temperature conditions. A conservative estimate of 30 mmol/min per site was used to estimate the flux into the water to be 1219–1355 mmol/s. The flux to the atmosphere was calculated by applying a bubble dissolution model taking release depth, temperature, gas composition, and bubble size spectra into account. The flux into the atmosphere (3930–4533 mol/d) or into the mixed layer (6186–6899 mol/d) from the 21.8 km2 large study area is three times higher than independently measured fluxes of dissolved methane for the same area using geochemical methods (1030–2495 mol/d). The amount of methane dissolving in the mixed layer is 2256–2366 mol/d. This close match shows that the hydroacoustic approach for extrapolating the number of seeps/m2 and the applied bubble dissolution model are suitable to extrapolate methane fluxes over larger areas.
Undesirable loss of weight is a major challenge in amyotrophic lateral sclerosis (ALS). However, little is known about loss of appetite in ALS patients.
We investigated loss of appetite in ALS ...patients by means of an online self-assessment and whether ALS-related symptoms were associated with it.
Loss of appetite in 51 ALS patients was assessed using the Council on Nutrition Appetite Questionnaire (CNAQ). Loss of appetite is defined as a CNAQ-score of 28 or less with a predicted weight loss of at least 5% within 6 months. We developed an Internet portal to facilitate self-assessment.
Approximately half of the ALS patients (47%, 24/51) suffered from severe loss of appetite; after 6 months this increased to nearly two-thirds (65%, 22/34). An average weight loss of 5% was found in the group with severe loss of appetite as compared to only 2% of patients with normal appetite. Interestingly, loss of appetite was associated with respiratory dysfunction (P=.001, R(2)=.223).
Loss of appetite was more common and more severe than expected. It was found to be an independent risk factor for unintended weight loss and may be related to dyspnea. The impact of severe loss of appetite on survival and quality of life should be established in further studies.
Eckernförde Bay in the Baltic Sea is well-known for the pockmarks areas which are located in the centre and off the southern shore-line of the bay emanating groundwater in a non-continuous but ...episodic way. Mobile underwater in situ gamma-ray spectroscopy is exploited proving that both 214Bi and 40K are efficient radiotracers for localization of seepage areas whenever either sediment is in mixture with the emanating fluid or resuspension of surface sediment occurs as a side effect of the fluid emanation.
•Application of mobile underwater in situ gamma-ray spectroscopy.•Localization of pockmarks emanating groundwater.•Radon progeny 214Bi proved an efficient radiotracer for localization purposes.•Potassium 40K is suggested as additional to radon radiotracers to localize fluid emanation areas whenever sediment is in mixture with the fluid or resuspension of sediment occurs.
The efficiency of the “benthic microbial methane filter” at marine cold seeps is controlled by diffusive sulfate supply from the overlying seawater and advective methane flux from deep reservoirs. ...High fluid fluxes reduce the penetration depth of sulfate and limit the filter to a very narrow zone close to the sediment‐water interface. Here, we introduce a new sediment‐flow‐through (SLOT) system, to mimic the balance between fluid/methane flow and sulfate supply in natural sediments. SLOT enables anaerobic incubations of intact sediment cores under natural flow regimes. In addition to traditional in‐ and outflow sampling, geochemical parameters can be monitored along the sediment core using microsensors and rhizons. In a first test run, two cores with gassy sediments from the Eckernförde Bay (Baltic Sea) were incubated and monitored for 310 days under low (11.2 cm y−1) and high fluid flow (112.1 cm y−1) conditions. Rates of anaerobic oxidation of methane (AOM) were one order of magnitude higher (3.07 mmol m−2 d−1) in the high flow compared to the low flow regime (0.29 mmol m−2 d−1), whereas methane efflux was twice as high (0.063 and 0.033 mmol m−2 d−1, respectively). Sediment profiles of sulfide, sulfate, total alkalinity, pH, redox, and other parameters offered important information on the nature and dynamics of the biogeochemical reactions in the sediment cores including methanotrophy, sulfate reduction, carbonate precipitation, and sulfide oxidation. The SLOT system proofed to be an effective device to study the temporal evolution of biogeochemical parameters in intact sediments subjected to advective fluid transport.
The new self-expanding, repositionable transcatheter heart valve (THV) system was designed for treatment of severe, symptomatic aortic stenosis in patients with high surgical risk.
The purpose of ...this study was to report 1-year outcomes of transcatheter aortic valve replacement with the new THV system.
This ongoing, international, multicenter study evaluated patients with severe, symptomatic aortic stenosis implanted with the THV via transfemoral access and follow-up at 30 days, 1 year, and annually through 5 years. The primary endpoint is all-cause mortality at 1 year; secondary endpoints include clinical outcomes and echocardiographic measurements, both adjudicated.
A total of 941 patients (82.4 ± 5.9 years; 65.7% female; Society of Thoracic Surgeons Predicted Risk of Operative Mortality score: 5.8%) were enrolled and underwent an implant at 61 sites in Europe, Australia, and Canada. At 1 year, Kaplan-Meier estimates for all-cause mortality, cardiovascular mortality, disabling stroke rates, and myocardial infarction were 12.1%, 6.6%, 2.2%, and 2.5%, respectively. Mean aortic transvalvular gradient and aortic valve area were 8.66 mm Hg and 1.75 cm
, respectively. Paravalvular leakage was moderate or higher in 2.6% of patients with no severe leakage. New pacemaker rates were 18.7% and 21.3% for pacemaker naïve patients at 30 days and 1 year, respectively. Functional class, exercise capacity, and quality of life improved significantly from baseline to 1 year.
Transcatheter aortic valve replacement with the new THV in patients who are at increased surgical risk is associated with low 1-year mortality and stroke rates. Favorable hemodynamic results at 1 year are observed with low transvalvular pressure gradient and incidence of significant paravalvular leakage. (5 Year Observation of Patients With PORTICO Valves PORTICO-I; NCT01802788).
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