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We report the case of a 40-year-old woman with a progressive right-sided hemiparesis. Standard MRI revealed a contrast-enhancing brain lesion within the left basal ganglia. Ffluoroethyl-L-tyrosine (F-FET) PET showed a distinct tracer uptake (lesion-to-brain ratio [LBR]: LBRmax = 2.03, LBRmean = 1.68) with a significant larger metabolic lesion volume than contrast-enhancement in MRI, indicating cerebral glioma. Surprisingly, histopathologic analysis demonstrated central nervous system toxoplasmosis with pronounced inflammatory reaction (reactive astrogliosis, microglia activation, macrophage, and T-lymphocyte infiltration), which was associated with strong LAT1/LAT2/CD98 expression. In conclusion, inflammatory brain lesions, such as cerebral toxoplasmosis, represent a potential pitfall of F-FET PET mimicking a brain tumor.

A patient who underwent multiple aortic operations suffered persistent infection of the ascending aorta and arch prosthesis and was finally treated with lifelong antibiotics. An 8-year follow-up with positron emission computed tomography is reported., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Goblet cell carcinoids belong to neuroendocrine tumors, according to the WHO classification. The tumors are diagnosed based on a typical histological pattern and using neuroendocrine markers. However, some tumors do not react with these markers and yet expression of proliferative markers is high. Do these tumors belong to G1 and G2 neuroendocrine tumors?, Methods: The sample comprised nine cases of tumors of the appendix identified by immunohistological methods as goblet cell carcinoids or adenocarcinoma ex goblet cell carcinoid., Results: In six cases, hematoxylin and eosin staining revealed tumors completely or 90% made of characteristic large tumor cells observed in typical goblet cell carcinoids. The remaining three cases were identified as adenocarcinomas arising ex goblet cell carcinoids. Immunohistological examination revealed that in four cases of typical goblet cell carcinoids, expression of neuroendocrine markers was low or completely negative. Yet in two cases, the Ki-67 proliferative index exceeded the 20% cut-off for inclusion in the G1 and G2 category., Conclusions: Goblet cell carcinoids are a heterogeneous group of tumors that may express neuroendocrine markers in a small number of tumor cells or are negative to these markers. However, high expression of the proliferative marker Ki-67 exceeds the criteria for G1 and G2 neuroendocrine tumors. It is our opinion that these tumors may be classified as a specific type of carcinoma.

The dielectric permittivity and properties of electrically active lattice resonances in nanotwinned BiFeO_{3} crystals have been studied theoretically using an earlier established interatomic potential. The results suggest that an array of 71° domain walls with about 2-5 nm spacing enhances the static permittivity of BiFeO_{3} by more than an order of magnitude. This enhancement is associated with an electrically active excitation, corresponding to a collective vibration of pinned domain walls at a remarkably high frequency of about 0.3 THz.

Differentiated thyroid cancer (DTC) is a rare malignant disease, although its incidence has increased over the last few decades. It derives from follicular thyroid cells. Generally speaking, the prognosis is excellent. If treatment according to the current guidelines is given, cases of recurrence or persistence are rare. DTC requires special expertise by the treating physician. In recent years, new therapeutic options for these patients have become available. For this article we performed a systematic literature review with special focus on the guidelines of the American Thyroid Association, the European Association of Nuclear Medicine, and the German Society of Nuclear Medicine. For DTC, surgery and radioiodine therapy followed by levothyroxine substitution remain the established therapeutic procedures. Even metastasized tumors can be cured this way. However, in rare cases of radioiodine-refractory tumors, additional options are to be discussed. These include strict suppression of thyroid-stimulating hormone (also known as thyrotropin, TSH) and external local radiotherapy. Systemic cytostatic chemotherapy does not play a significant role. Recently, multikinase or tyrosine kinase inhibitors have been approved for the treatment of radioiodine-refractory DTC. Although a benefit for overall survival has not been shown yet, these new drugs can slow down tumor progression. However, they are frequently associated with severe side effects and should be reserved for patients with threatening symptoms only., Competing Interests: The authors declare no conflict of interest.

Aim: Updated presentation of the spectrum of nuclear medicine in-vivo examinations and therapies from officially available statistics on out-patient and in-patient care as well as trends of structural data on nuclear medicine in Germany., Methods: Data from the German Federal Health Monitoring, from the frequency statistics of the statutory health insurance for out-patients and from the German Medical Association were used and supplemented by data from selective literature searches., Results: In descending order, thyroid, bone and cardiac scans continue to be the most frequent nuclear medicine procedures. With a marked increase of PET/CT and SPECT/CT, the number of basic scintigraphies is declining. Cardiac, lung and brain scans as well as lymph scintigraphies are increasingly requested, bone and thyroid scan decrease. The consultation of nuclear medicine physicians in private practices is increasing by 4 % per year (2009: 2 164 664; 2015: 2 687 359). The number of nuclear medicine physicians in the out-patient sector rose significantly (2009: 756, 2015: 939, growth 24 %) and has remained constant due to restrictions since 2013. The specialist recognitions of women in nuclear medicine increased (proportion currently 46 %). In hospitals, more PET(/CT) scanners (2009: 97; 2015: 125) and fewer gamma cameras (2009: 594; 2015: 550) are operated. The number of non-thyroid (and also out-patient) radionuclide therapies continued to increase., Conclusion: With increased use of hybrid technologies, the nuclear medicine spectrum shows positive trends especially in nuclear cardiology and extra-thyroid therapy. These developments must be taken into account when amending regulations of specialist training and medical student teaching.

This study aimed to investigate the pharmaceutical performance of an indomethacin-polyvinylpyrrolidone (PVP) glass solution applied using fluid bed processing as a layer on inert sucrose spheres and subsequently top-coated with a release rate controlling membrane consisting of either ethyl cellulose or Eudragit RL. The implications of the addition of a pore former (PVP) and the coating medium (ethanol or water) on the diffusion and release behavior were also considered. In addition, the role of a charge interaction between drug and controlled release polymer on the release was investigated. Diffusion experiments pointed to the influence of pore former concentration, rate controlling polymer type, and coating solvent on the permeability of the controlled release membranes. This can be translated to drug release tests, which show the potential of diffusion tests as a preliminary screening test and that diffusion is the main factor influencing release. Drug release tests also showed the effect of coating layer thickness. A charge interaction between INDO and ERL was demonstrated, but this had no negative effect on drug release. The higher diffusion and release observed in ERL-based rate controlling membranes was explained by a higher hydrophilicity, compared to EC.

Several years ago, we detected the formation of multicellular spheroids in experiments with human thyroid cancer cells cultured on the Random Positioning Machine (RPM), a ground-based model to simulate microgravity by continuously changing the orientation of samples. Since then, we have studied cellular mechanisms triggering the cells to leave a monolayer and aggregate to spheroids. Our work focused on spheroid-related changes in gene expression patterns, in protein concentrations, and in factors secreted to the culture supernatant during the period when growth is altered. We detected that factors inducing angiogenesis, the composition of integrins, the density of the cell monolayer exposed to microgravity, the enhanced production of caveolin-1, and the nuclear factor kappa B p65 could play a role during spheroid formation in thyroid cancer cells. In this study, we performed a deep proteome analysis on FTC-133 thyroid cancer cells cultured under conditions designed to encourage or discourage spheroid formation. The experiments revealed more than 5900 proteins. Their evaluation confirmed and explained the observations mentioned above. In addition, we learned that FTC-133 cells growing in monolayers or in spheroids after RPM-exposure incorporate vinculin, paxillin, focal adhesion kinase 1, and adenine diphosphate (ADP)-ribosylation factor 6 in different ways into the focal adhesion complex.

Batch and saturated soil column experiments were conducted to investigate sorption and mobility of two 14 C-labeled contaminants, the hydrophobic chlordecone (CLD) and the sulfadiazine (SDZ), in the absence or presence of functionalized multi-walled carbon nanotubes (MWCNTs). The transport behaviors of CLD, SDZ, and MWCNTs were studied at environmentally relevant concentrations (0.1-10 mg L -1 ) and they were applied in the column studies at different times. The breakthrough curves and retention profiles were simulated using a numerical model that accounted for the advective-dispersive transport of all compounds, attachment/detachment of MWCNTs, equilibrium and kinetic sorption of contaminants, and co-transport of contaminants with MWCNTs. The experimental results indicated that the presence of mobile MWCNTs facilitated remobilization of previously deposited CLD and its co-transport into deeper soil layers, while retained MWCNTs enhanced SDZ deposition in the topsoil layers due to the increased adsorption capacity of the soil. The modeling results then demonstrated that the mobility of engineered nanoparticles (ENPs) in the environment and the high affinity and entrapment of contaminants to ENPs were the main reasons for ENP-facilitated contaminant transport. On the other hand, immobile MWCNTs had a less significant impact on the contaminant transport, even though they were still able to enhance the adsorption capacity of the soil., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Saturated soil column experiments were conducted to investigate the transport, retention, and release behavior of a low concentration (1 mg L -1 ) of functionalized 14 C-labeled multi-walled carbon nanotubes (MWCNTs) in a natural soil under various solution chemistries. Breakthrough curves (BTCs) for MWCNTS exhibited greater amounts of retardation and retention with increasing solution ionic strength (IS) or in the presence of Ca 2+ in comparison to K + , and retention profiles (RPs) for MWCNTs were hyper-exponential in shape. These BTCs and RPs were well described using the advection-dispersion equation with a term for time- and depth-dependent retention. Fitted values of the retention rate coefficient and the maximum retained concentration of MWCNTs were higher with increasing IS and in the presence of Ca 2+ in comparison to K + . Significant amounts of MWCNT and soil colloid release was observed with a reduction of IS due to expansion of the electrical double layer, especially following cation exchange (when K + displaced Ca 2+ ) that reduced the zeta potential of MWCNTs and the soil. Analysis of MWCNT concentrations in different soil size fractions revealed that >23.6% of the retained MWCNT mass was associated with water-dispersible colloids (WDCs), even though this fraction was only a minor portion of the total soil mass (2.38%). More MWCNTs were retained on the WDC fraction in the presence of Ca 2+ than K + . These findings indicated that some of the released MWCNTs by IS reduction and cation exchange were associated with the released clay fraction, and suggests the potential for facilitated transport of MWCNT by WDCs., (Published by Elsevier Ltd.)

O-(2- 18 F-fluoroethyl)-l-tyrosine ( 18 F-FET) PET is a well-established method increasingly used for diagnosis, treatment planning, and monitoring in gliomas. Epileptic activity, frequently occurring in glioma patients, can influence MRI findings. Whether seizures also affect 18 F-FET PET imaging is currently unknown. The aim of this retrospective analysis was to investigate the brain amino acid metabolism during epileptic seizures by 18 F-FET PET and to elucidate the pathophysiologic background., Methods: Ten patients with 11 episodes of serial seizures or status epilepticus, who underwent MRI and 18 F-FET PET, were studied. The main diagnosis was glioma World Health Organization grade II-IV (n = 8); 2 patients suffered from nonneoplastic diseases. Immunohistochemical assessment of LAT1/LAT2/CD98 amino acid transporters was performed in seizure-affected cortex (n = 2) and compared with glioma tissues (n = 3)., Results: All patients exhibited increased seizure-associated strict gyral 18 F-FET uptake, which was reversible in follow-up studies or negative shortly before and without any histologic or clinical signs of tumor recurrence. 18 F-FET uptake corresponded to structural MRI changes, compatible with cortical vasogenic and cytotoxic edema, partial contrast enhancement, and hyperperfusion. Patients with prolonged postictal symptoms lasting up to 8 wk displayed intensive and widespread (≥ 1 lobe) cortical 18 F-FET uptake. LAT1/LAT2/CD98 was strongly expressed in neurons and endothelium of seizure-affected brains and less in reactive astrocytosis., Conclusion: Seizure activity, in particular status epilepticus, increases cerebral amino acid transport with a strict gyral 18 F-FET uptake pattern. Such periictal pseudoprogression represents a potential pitfall of 18 F-FET PET and may mimic brain tumor. Our data also indicate a seizure-induced upregulation of neuronal, endothelial, and less astroglial LAT1/LAT2/CD98 amino acid transporter expression., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

The Centers for Disease Control and Prevention (CDC) in the United States has declared insufficient sleep a "public health problem." Indeed, according to a recent CDC study, more than a third of American adults are not getting enough sleep on a regular basis. However, insufficient sleep is not exclusively a US problem, and equally concerns other industrialised countries such as the United Kingdom, Japan, Germany, or Canada. According to some evidence, the proportion of people sleeping less than the recommended hours of sleep is rising and associated with lifestyle factors related to a modern 24/7 society, such as psychosocial stress, alcohol consumption, smoking, lack of physical activity and excessive electronic media use, among others. This is alarming as insufficient sleep has been found to be associated with a range of negative health and social outcomes, including success at school and in the labour market. Over the last few decades, for example, there has been growing evidence suggesting a strong association between short sleep duration and elevated mortality risks. Given the potential adverse effects of insufficient sleep on health, well-being and productivity, the consequences of sleep-deprivation have far-reaching economic consequences. Hence, in order to raise awareness of the scale of insufficient sleep as a public-health issue, comparative quantitative figures need to be provided for policy- and decision-makers, as well as recommendations and potential solutions that can help tackling the problem.

Transport and retention behavior of multi-walled carbon nanotubes (MWCNTs) was studied in mixtures of negatively charged quartz sand (QS) and positively charged goethite-coated sand (GQS) to assess the role of chemical heterogeneity. The linear equilibrium sorption model provided a good description of batch results, and the distribution coefficients (K D ) drastically increased with the GQS fraction that was electrostatically favorable for retention. Similarly, retention of MWCNTs increased with the GQS fraction in packed column experiments. However, calculated values of K D on GQS were around 2 orders of magnitude smaller in batch than packed column experiments due to differences in lever arms associated with hydrodynamic and adhesive torques at microscopic roughness locations. Furthermore, the fraction of the sand surface area that was favorable for retention (S f ) was much smaller than the GQS fraction because nanoscale roughness produced shallow interactions that were susceptible to removal. These observations indicate that only a minor fraction of the GQS was favorable for MWCNT retention. These same observations held for several different sand sizes. Column breakthrough curves were always well described using an advective-dispersive transport model that included retention and blocking. However, depth-dependent retention also needed to be included to accurately describe the retention profile when the GQS fraction was small. Results from this research indicate that roughness primarily controlled the retention of MWCNTs, although goethite surfaces played an important secondary role.

The past few decades have seen a number of medical breakthroughs that enabled the effective treatment of a range of conditions, transforming them from fatal into manageable ones. Examples include certain cancers and HIV. Conversely, progress on dementia has been limited. There are currently no treatments that will cure or even alter the progressive course of dementia, despite ongoing research investigating new therapies and care options. The UK Department of Health is interested in the potential to learn from other disease areas to better understand the particular social, economic, political, legislative and scientific contexts that have contributed to accelerating progress and breakthroughs in treatment. Such learning could helpfully inform dementia research and innovation efforts, and help identify levers for supportive policy development. This project analysed breakthroughs in the treatment of four selected conditions of ill health and seeks to identify potentially transferable lessons for the dementia context. Using evidence review and key informant interviews we sought to identify the series of "events" that eventually led to a given breakthrough, and the key milestones in the process that have helped improve understanding and potential for treatment. We also aimed to capture the temporal and causal relationships between "notable" events looking at a variety of factors implicated in the breakthrough pathway. The focus of this work was on political, economic, social, scientific and technological, and legal, regulatory and environmental factors.

Experiencing real weightlessness in space is a dream for many of us who are interested in space research. Although space traveling fascinates us, it can cause both short-term and long-term health problems. Microgravity is the most important influence on the human organism in space. The human body undergoes dramatic changes during a long-term spaceflight. In this review, we will mainly focus on changes in calcium, sodium and bone metabolism of space travelers. Moreover, we report on the current knowledge on the mechanisms of bone loss in space, available models to simulate the effects of microgravity on bone on Earth as well as the combined effects of microgravity and cosmic radiation on bone. The available countermeasures applied in space will also be evaluated., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The aggregation of mostly antibody light chain variable (VL) domains into amyloid fibrils in various tissues is the main cause of death in systemic amyloid light chain amyloidosis. Point mutations within the domain are important to shift the VL into the fibrillar pathway, but why and how only some site-specific mutations achieve this still remains elusive. We show here that both destabilizing and surprisingly stable mutants readily predispose an amyloid-resistant VL domain to amyloid formation. The decreased thermodynamic stability of the destabilizing mutant results in the accumulation of non-native intermediates that readily populate the amyloid state. Interestingly, the stable mutants establish site-specific non-native interactions with especially nearby serine/threonine residues that unexpectedly do not affect the folding behavior of the VL domain but rather readily induce and stabilize the fibril structure, a previously unrecognized mechanism. These findings provide a new concept for the molecular mechanism of amyloid fibril formation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

RAND Europe undertook a systematic review of the evidence of effectiveness and cost effectiveness on changing the public's risk related behaviour pertaining to antimicrobial use to inform the development of a NICE public health guideline aimed at delaying antimicrobial resistance (AMR). The review considered educational interventions targeting individuals, communities or the general public delivered via any mode. Specifically, it aimed to address: 1. Which educational interventions are effective and cost-effective in changing the public's behaviour to ensure they only ask for antimicrobials when appropriate and use them correctly? 2. Which educational interventions are effective and cost-effective in changing the public's behaviour to prevent infection and reduce the spread of antimicrobial resistance? Overall, 60 studies met the inclusion criteria; 29 related to research question 1, and 36 related to research question 2 (five studies were applicable to both). The key findings are summarised in "Evidence Statements" in accordance with NICE guidelines. Evidence Statements provide a high level overview of the key features of the evidence including: the number of studies, the quality of evidence, and the direction of the estimated effect followed by a brief summary of each of the supporting studies. Studies are grouped into Evidence Statements by setting and intervention.

A 64-year-old patient developed sudden hypoglycemia leading to unconsciousness. Hypoglycemic episodes recurred on several occasions but were not accompanied by unconsciousness. Magnetic resonance imaging revealed a liver tumor in the right lobe sized 20.0 × 14.6 × 19.0 cm. No other masses were detected. Right hemihepatectomy was indicated but could not be performed due to heavy bleeding near the tumor. Histological examination showed a relatively cellular tumor made of elongated bland cells. The mitotic index was fewer than 4 mitoses per 10 HPF. The tumor was without necrosis or hemorrhage. The excised tumor was not encapsulated and showed no signs of invasive growth. On immunohistological examination, the tumor expressed NSE, CD34, CD99, Bcl2 and STAT6; Ki-67 was positive in approximately 20% of the cells. Both the histological pattern and immunophenotype were suggestive of solitary fibrous tumor of the liver. Given its size, cellularity and relatively high expression of the proliferation marker Ki-67, the tumor was classified as potentially malignant. The patient underwent embolization of arteries supplying the tumor with blood. The effect of the procedure on the tumor will only be assessed later. Hypoglycemia has resolved and the patient feels well.

Background: The two α-crystallins (αA- and αB-crystallin) are major components of our eye lenses. Their key function there is to preserve lens transparency which is a challenging task as the protein turnover in the lens is low necessitating the stability and longevity of the constituent proteins. α-Crystallins are members of the small heat shock protein family. αB-crystallin is also expressed in other cell types., Scope of the Review: The review summarizes the current concepts on the polydisperse structure of the α-crystallin oligomer and its chaperone function with a focus on the inherent complexity and highlighting gaps between in vitro and in vivo studies., Major Conclusions: Both α-crystallins protect proteins from irreversible aggregation in a promiscuous manner. In maintaining eye lens transparency, they reduce the formation of light scattering particles and balance the interactions between lens crystallins. Important for these functions is their structural dynamics and heterogeneity as well as the regulation of these processes which we are beginning to understand. However, currently, it still remains elusive to which extent the in vitro observed properties of α-crystallins reflect the highly crowded situation in the lens., General Significance: Since α-crystallins play an important role in preventing cataract in the eye lens and in the development of diverse diseases, understanding their mechanism and substrate spectra is of importance. To bridge the gap between the concepts established in vitro and the in vivo function of α-crystallins, the joining of forces between different scientific disciplines and the combination of diverse techniques in hybrid approaches are necessary. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Thyroid cancer is the most common type of endocrine neoplasia. Differentiated thyroid carcinoma (DTC) represents 94% of all thyroid cancer types. Approximately 20% experience local recurrence and 10% distant metastasis. The recurrent DTC often becomes less differentiated, loses the iodine uptake capability and consequently loses the radioactive iodine treatment option. Under these circumstances survivability drops below 10% at 10 years. The treatment options for dedifferentiated thyroid cancers are extremely limited. This category sometimes referred to as poorly differentiated thyroid cancer (PDTC), is characterised by a missing response to radioiodine treatment and a remarkably reduced survivability. Therefore, new drugs have been developed to fill this gap in treatment., Methods: The goal of this work is to review the effects and roles of the multikinase inhibitors sorafenib, sunitinb and lenatinib in thyroid cancer., Results: The new tyrosine kinase inhibitors (TKIs) aimed to inhibit tumour angiogenesis. Current clinical trials with novel drugs have shown promising results. A phase III trial (DECISION) of sorafenib in radioiodine (RAI)-refractory thyroid cancer showed a median progression-free survival (PFS) of 10.8 months in the sorafenib group, compared to 5.8 months in the placebo group. Sunitinib, another TKI, exhibited significant antitumour effects in patients with advanced DTC. Nevertheless, treatment with TKIs can lead to the development of resistance against these anti-angiogenic treatments, partly due to compensatory mechanisms. Lenvatinib, the recently approved drug for RAI-refractory thyroid cancer, blocks a different receptor than the currently available drugs. Lenvatinib inhibits fibroblast growth factor receptor (FGFR), as well as other receptors. FGFR plays a key role in the development of resistance against anti-angiogenic drugs. In a phase III trial (SELECT) on RAI-refractory DTC, the lenvatinib group showed a PFS of 18.3 months, compared to 3.6 months in the placebo group. This led to the approval of lenvatinib, the first drug capable of reversing anti-angiogenic mechanisms., Conclusion: The frequently adverse effects seen in TKI treatment require further investigation. A well-adjusted balance between efficacy and adverse effects is desirable. No effects on overall survival were reported. Therefore, further studies are required.

The kinase/endonuclease IRE1 is the most conserved signal transducer of the unfolded protein response (UPR), an intracellular signaling network that monitors and regulates the protein folding capacity of the endoplasmic reticulum (ER). Upon sensing protein folding perturbations in the ER, IRE1 initiates the unconventional splicing of XBP1 mRNA culminating in the production of the transcription factor XBP1s, which expands the ER's protein folding capacity. We show that an RNA-intrinsic conformational change causes the intron of XBP1 mRNA to be ejected and the exons to zipper up into an extended stem, juxtaposing the RNA ends for ligation. These conformational rearrangements are important for XBP1 mRNA splicing in vivo. The features that point to such active participation of XBP1 mRNA in the splicing reaction are highly conserved throughout metazoan evolution, supporting their importance in orchestrating XBP1 mRNA processing with efficiency and fidelity., (© 2015 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Small heat-shock proteins, including αB-crystallin (αB), play an important part in protein homeostasis, because their ATP-independent chaperone activity inhibits uncontrolled protein aggregation. Mechanistic details of human αB, particularly in its client-bound state, have been elusive so far, owing to the high molecular weight and the heterogeneity of these complexes. Here we provide structural insights into this highly dynamic assembly and show, by using state-of-the-art NMR spectroscopy, that the αB complex is assembled from asymmetric building blocks. Interaction studies demonstrated that the fibril-forming Alzheimer's disease Aβ1-40 peptide preferentially binds to a hydrophobic edge of the central β-sandwich of αB. In contrast, the amorphously aggregating client lysozyme is captured by the partially disordered N-terminal domain of αB. We suggest that αB uses its inherent structural plasticity to expose distinct binding interfaces and thus interact with a wide range of structurally variable clients.

In this study we focused on gravity-sensitive proteins of two human thyroid cancer cell lines (ML-1; RO82-W-1), which were exposed to a 2D clinostat (CLINO), a random positioning machine (RPM) and to normal 1g-conditions. After a three (3d)- or seven-day-culture (7d) on the two devices, we found both cell types growing three-dimensionally within multicellular spheroids (MCS) and also cells remaining adherent (AD) to the culture flask, while 1g-control cultures only formed adherent monolayers, unless the bottom of the culture dish was covered by agarose. In this case, the cytokines IL-6 and IL-8 facilitated the formation of MCS in both cell lines using the liquid-overlay technique at 1g. ML-1 cells grown on the RPM or the CLINO released amounts of IL-6 and MCP-1 into the supernatant, which were significantly elevated as compared to 1g-controls. Release of IL-4, IL-7, IL-8, IL-17, eotaxin-1 and VEGF increased time-dependently, but was not significantly influenced by the gravity conditions. After 3d on the RPM or the CLINO, an accumulation of F-actin around the cellular membrane was detectable in AD cells of both cell lines. IL-6 and IL-8 stimulation of ML-1 cells for 3d and 7d influenced the protein contents of ß1-integrin, talin-1, Ki-67, and beta-actin dose-dependently in adherent cells. The ß1-integrin content was significantly decreased in AD and MCS samples compared with 1g, while talin-1 was higher expressed in MCS than AD populations. The proliferation marker Ki-67 was elevated in AD samples compared with 1g and MCS samples. The ß-actin content of R082-W-1 cells remained unchanged. ML-1 cells exhibited no change in ß-actin in RPM cultures, but a reduction in CLINO samples. Thus, we concluded that simulated microgravity influences the release of cytokines in follicular thyroid cancer cells, and the production of ß1-integrin and talin-1 and predicts an identical effect under real microgravity conditions.

Communication systems are exposed to two different pressures: a pressure for transmission efficiency, such that messages are simple to produce and perceive, and a pressure for referential efficiency, such that messages are easy to understand with their intended meaning. A solution to the first pressure is combinatoriality--the recombination of a few basic meaningless forms to express an infinite number of meanings. A solution to the second is iconicity--the use of forms that resemble what they refer to. These two solutions appear to be incompatible with each other, as iconic forms are ill-suited for use as meaningless combinatorial units. Furthermore, in the early stages of a communication system, when basic referential forms are in the process of being established, the pressure for referential efficiency is likely to be particularly strong, which may lead it to trump the pressure for transmission efficiency. This means that, where iconicity is available as a strategy, it is likely to impede the emergence of combinatoriality. Although this hypothesis seems consistent with some observations of natural language, it was unclear until recently how it could be soundly tested. This has changed thanks to the development of a line of research, known as Experimental Semiotics, in which participants construct novel communication systems in the laboratory using an unfamiliar medium. We conducted an Experimental Semiotic study in which we manipulated the opportunity for iconicity by varying the kind of referents to be communicated, while keeping the communication medium constant. We then measured the combinatoriality and transmission efficiency of the communication systems. We found that, where iconicity was available, it provided scaffolding for the construction of communication systems and was overwhelmingly adopted. Where it was not available, however, the resulting communication systems were more combinatorial and their forms more efficient to produce. This study enriches our understanding of the fundamental design principles of human communication and contributes tools to enrich it further., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Based on small-scale laboratory and field-scale lysimeter experiments, the sorption and biodegradation of sulfonamide sulfadiazine (SDZ) were investigated in unsaturated sandy and silty-clay soils. Sorption and biodegradation were low in the laboratory, while the highest leaching rates were observed when SDZ was mixed with manure. The leaching rate decreased when SDZ was mixed with pure water, and was smallest with the highest SDZ concentrations. In the laboratory, three transformation products (TPs) developed after an initial lag phase. However, the amount of TPs was different for different mixing-scenarios. The TP 2-aminopyrimidine was not observed in the laboratory, but was the most prevalent TP at the field scale. Sorption was within the same range at the laboratory and field scales. However, distinctive differences occurred with respect to biodegradation, which was higher in the field lysimeters than at the laboratory scale. While the silty-clay soil favored sorption of SDZ, the sandy, and thus highly permeable, soil was characterized by short half-lives and thus a quick biodegradation of SDZ. For 2-aminopyrimidine, half-lives of only a few days were observed. Increased field-scale biodegradation in the sandy soil resulted from a higher water and air permeability that enhanced oxygen transport and limited oxygen depletion. Furthermore, low pH was more important than the organic matter and clay content for increasing the biodegradation of SDZ. A numerical analysis of breakthrough curves of bromide, SDZ, and its TPs showed that preferential flow pathways strongly affected the solute transport within shallow parts of the soil profile at the field scale. However, this effect was reduced in deeper parts of the soil profile. Due to high field-scale biodegradation in several layers of both soils, neither SDZ nor 2-aminopyrimidine was detected in the discharge of the lysimeter at a depth of 1m. Synthetic 50 year long simulations, which considered the application of manure with SDZ for general agricultural practices in Germany and humid climate conditions, showed that the concentration of SDZ decreased below 0.1 μg/L in both soils below the depth of 50 cm., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Real and simulated microgravity induce a variety of changes in human cells. Most importantly, changes in the cytoskeleton have been noted, and studies on microtubules have shown that they are gravisensitive. This study focuses on the effects of short-term real microgravity on gene expression, protein content, and cytoskeletal structure of human chondrocytes. We cultivated human chondrocytes, took them along a parabolic flight during the 24th Deutsches Zentrum für Luft- und Raumfahrt Parabolic (DLR) Flight Campaign, and fixed them after the 1st and the 31st parabola. Immunofluorescence microscopy revealed no changes after the 1st parabola, but disruptions of β-tubulin, vimentin, and cytokeratin networks after the 31st parabola. No F-actin stress fibers were detected even after 31 parabolas. Furthermore, mRNA and protein quantifications after the 31st parabola showed a clear up-regulation of cytoskeletal genes and proteins. The mRNAs were significantly up-regulated as follows: TUBB, 2-fold; VIM, 1.3-fold; KRT8, 1.8-fold; ACTB, 1.9-fold; ICAM1, 4.8-fold; OPN, 7-fold; ITGA10, 1.5-fold; ITGB1, 1.2-fold; TGFB1, 1.5-fold; CAV1, 2.6-fold; SOX9, 1.7-fold; BMP-2, 5.3-fold. However, SOX5 (-25%) and SOX6 (-28%) gene expression was decreased. Contrary, no significant changes in gene expression levels were observed during vibration and hypergravity experiments. These data suggest that short-term microgravity affects the gene expression of distinct proteins. In contrast to poorly differentiated follicular thyroid cancer cells or human endothelial cells, chondrocytes only exert moderate cytoskeletal alterations. The up-regulation of BMP-2, TGF-β1, and SOX9 in chondrocytes may play a key role in preventing cytoskeletal alterations., (© FASEB.)

Sharks and other cartilaginous fish are the phylogenetically oldest living organisms that rely on antibodies as part of their adaptive immune system. They produce the immunoglobulin new antigen receptor (IgNAR), a homodimeric heavy chain-only antibody, as a major part of their humoral adaptive immune response. Here, we report the atomic resolution structure of the IgNAR constant domains and a structural model of this heavy chain-only antibody. We find that despite low sequence conservation, the basic Ig fold of modern antibodies is already present in the evolutionary ancient shark IgNAR domains, highlighting key structural determinants of the ubiquitous Ig fold. In contrast, structural differences between human and shark antibody domains explain the high stability of several IgNAR domains and allowed us to engineer human antibodies for increased stability and secretion efficiency. We identified two constant domains, C1 and C3, that act as dimerization modules within IgNAR. Together with the individual domain structures and small-angle X-ray scattering, this allowed us to develop a structural model of the complete IgNAR molecule. Its constant region exhibits an elongated shape with flexibility and a characteristic kink in the middle. Despite the lack of a canonical hinge region, the variable domains are spaced appropriately wide for binding to multiple antigens. Thus, the shark IgNAR domains already display the well-known Ig fold, but apart from that, this heavy chain-only antibody employs unique ways for dimerization and positioning of functional modules.

The multikinase inhibitor sunitinib (S) seems to have promising potential in the treatment of thyroid cancer. We focused on the impact of S and/or irradiation (R) on mechanisms of apoptosis in follicular thyroid cancer cells. The effects of R, S and their combination were evaluated 2 and 4 days after treatment, using the human thyroid cancer cell line CGTH W-1. The transcription of genes involved in the regulation of apoptosis was investigated using quantitative real-time PCR. Western blot analyses of caspases and survivin were also performed. S elevated BAX (day 4), CASP9, CASP3, BIRC5 (day 4) and PRKACA (day 4) gene expression, whereas the mRNAs of BCL2, CASP8, PRKCA, ERK1, and ERK2 were not significantly changed. S, R and R+S clearly induced caspase-9 protein and elevated caspase-3 activity. Survivin was down-regulated at day 4 in control cells and the expression was blunted by S treatment. R+S induced survivin expression at day 2 followed by a reduction at day 4 of treatment. Sunitinib and the combined application with radiation induced apoptosis in follicular thyroid cancer cells via the intrinsic pathway of apoptosis. In addition, sunitinib might induce apoptosis via decreased expression of the anti-apoptotic protein survivin. These findings suggest the potential use of sunitinib for the treatment of poorly differentiated follicular thyroid carcinomas.

This study focuses on the effects of short-term [22 s, parabolic flight campaign (PFC)] and long-term (10 d, Shenzhou 8 space mission) real microgravity on changes in cytokine secretion and gene expression patterns in poorly differentiated thyroid cancer cells. FTC-133 cells were cultured in space and on a random positioning machine (RPM) for 10 d, to evaluate differences between real and simulated microgravity. Multianalyte profiling was used to evaluate 128 secreted cytokines. Microarray analysis revealed 63 significantly regulated transcripts after 22 s of microgravity during a PFC and 2881 after 10 d on the RPM or in space. Genes in several biological processes, including apoptosis (n=182), cytoskeleton (n=80), adhesion/extracellular matrix (n=98), proliferation (n=184), stress response (n=268), migration (n=63), angiogenesis (n=39), and signal transduction (n=429), were differentially expressed. Genes and proteins involved in the regulation of cancer cell proliferation and metastasis, such as IL6, IL8, IL15, OPN, VEGFA, VEGFD, FGF17, MMP2, MMP3, TIMP1, PRKAA, and PRKACA, were similarly regulated under RPM and spaceflight conditions. The resulting effect was mostly antiproliferative. Gene expression during the PFC was often regulated in the opposite direction. In summary, microgravity is an invaluable tool for exploring new targets in anticancer therapy and can be simulated in some aspects in ground-based facilities.

Purpose: To describe a chairside method for producing implant guides based solely on digital data and present a first assessment of in vitro accuracy on plaster models., Material and Methods: Twenty-four implants were planned and pilot drillings were performed according to a new protocol, which is based on the registration of CBCT and CAD/CAM data. Chairside-milled one-piece drill guides were used to transfer the virtual plan into reality. Accuracy measurements were acquired., Results: Chairside-milled drill guides were successfully fabricated and accuracy for pilot drillings was between 0.17 and 1.3 mm., Conclusion: Within the limits of this experimental study, chairside-milled drill guides are feasible and do not require any preparation before CBCT scanning.

Unlabelled: Uterine tumors resembling ovarian sex cord tumors (UTROSCT) have an uncertain histogenesis. Although generally considered to be benign, they metastasize in some cases. We report the case of a 53-year-old woman who presented with vaginal bleeding. Clinical examination revealed a tumor sized 1.5 cm in diameter localized in the subendometrial region of the uterine wall. Histologically, the tumor consisted of epithelioid oval cells arranged in solid nests, trabeculae and ribbons. Immunohistochemically, approximately 1% of tumor cells expressed strong desmin positivity, calponin in 10% of cells, WT1 in 80% cells, and Ki-67 was positive in about 5 % of tumor cells. All the other immunohistochemical reactions applied including anti-cytokeratin antibodies were negative. The RT-PCR method for identification of the JAZF1-JJAZ1 fusion transcript was negative. In one lymph node in the right iliac artery region, a metastasis of UTROSCT was found. This finding adds to the previously reported UTROSCT cases with metastatic spread., Keywords: uterine tumors resembling ovarian sex cord tumors - UTROSCT - metastasis - lymph node.

A 74-year-old woman was admitted in a serious condition due to the failing right heart. A CT scan revealed a tumor infiltration through the interventricular septum in the right heart, spreading from the apex as far as under the tricuspid valve. The tumor penetrated into the conus of the pulmonary artery, bulging and markedly narrowing the lumen. As a result of the tumor infiltration, the patient died from cardiac failure. Histological examination of the tumor revealed atypical elongated cells and areas of large cells with significantly enlarged hyperchromatic and lobulated nuclei. In some portions, the tumors had a biphasic appearance. The tumor cells resembled epithelial tissue but immunohistological analyses to detect cytokeratins yielded negative results. The elongated cells expressed desmin and smooth muscle actin. A vast majority of the tumor was solid or hard, histologically corresponding to osteosarcoma. Later, it was found that the patient undergone right-sided mastectomy for a malignant phyllodes tumor with osteosarcomatous differentiation three years previously. The metastasis to the heart was the only metastasis detected by the autopsy.

How microgravity affects the biology of human cells and the formation of 3D cell cultures in real and simulated microgravity (r- and s-µg) is currently a hot topic in biomedicine. In r- and s-µg, various cell types were found to form 3D structures. This review will focus on the current knowledge of tissue engineering in space and on Earth using systems such as the random positioning machine (RPM), the 2D-clinostat, or the NASA-developed rotating wall vessel bioreactor (RWV) to create tissue from bone, tumor, and mesenchymal stem cells. To understand the development of 3D structures, in vitro experiments using s-µg devices can provide valuable information about modulations in signal-transduction, cell adhesion, or extracellular matrix induced by altered gravity conditions. These systems also facilitate the analysis of the impact of growth factors, hormones, or drugs on these tissue-like constructs. Progress has been made in bone tissue engineering using the RWV, and multicellular tumor spheroids (MCTS), formed in both r- and s-µg, have been reported and were analyzed in depth. Currently, these MCTS are available for drug testing and proteomic investigations. This review provides an overview of the influence of µg on the aforementioned cells and an outlook for future perspectives in tissue engineering.

Reactive oxygen species are important components of the immune response. Hypochlorite (HOCl) is produced by neutrophils to kill invading microorganisms. The bactericidal activity of HOCl is due to proteome-wide unfolding and oxidation of proteins at cysteine and methionine residues. Escherichia coli cells are protected from HOCl-killing by the previously identified dodecameric transcription factor HypT (YjiE). Here, we aimed to unravel whether HOCl activates HypT directly or via a reaction product of HOCl with a cellular component. Bacterial viability assays and analysis of target gene regulation indicate that HypT is highly specific to activation by HOCl and that no reaction products of HOCl such as monochloramine, hydroxyl radicals, or methionine sulfoxide activate HypT in vivo. Surprisingly, purified HypT lost its DNA-binding activity upon incubation with HOCl or reaction products that oxidize HypT to form a disulfide-linked dimer, and regained DNA-binding activity upon reduction. Thus, we postulate that the cysteines in HypT contribute to control the DNA-binding activity of HypT in vitro. HypT contains five cysteine residues; a HypT mutant with all cysteines substituted by serine is aggregation-prone and forms tetramers in addition to the typical dodecamers. Using single and multiple cysteine-to-serine mutants, we identified Cys150 to be required for stability and Cys4 being important for oligomerization of HypT to dodecamers. Further, oxidation of Cys4 is responsible for the loss of DNA-binding of HypT upon oxidation in vitro. It appears that Cys4 oxidation upon conditions that are insufficient to stimulate the DNA-binding activity of HypT prevents unproductive interactions of HypT with DNA. Thus, Cys4 oxidation may be a check point in the activation process of HypT.

The small heat shock protein αB-crystallin is an oligomeric molecular chaperone that binds aggregation-prone proteins. As a component of the proteostasis system, it is associated with cataract, neurodegenerative diseases, and myopathies. The structural determinants for the regulation of its chaperone function are still largely elusive. Combining different experimental approaches, we show that phosphorylation-induced destabilization of intersubunit interactions mediated by the N-terminal domain (NTD) results in the remodeling of the oligomer ensemble with an increase in smaller, activated species, predominantly 12-mers and 6-mers. Their 3D structures determined by cryo-electron microscopy and biochemical analyses reveal that the NTD in these species gains flexibility and solvent accessibility. These modulated properties are accompanied by an increase in chaperone activity in vivo and in vitro and a more efficient cooperation with the heat shock protein 70 system in client folding. Thus, the modulation of the structural flexibility of the NTD, as described here for phosphorylation, appears to regulate the chaperone activity of αB-crystallin rendering the NTD a conformational sensor for nonnative proteins.

Background: The objective of the study was to report a rare case of primary neuroendocrine carcinoma of the right kidney in a 36 year old male., Methods: The patient was clinically assessed; CT and OctreoScan scintigraphy were performed and levels of 5-HIAA, vanillylmandelic acid and NSE were determined. The tumor and metastases were histologically and immunohistochemically examined., Results: The imaging methods showed a cystic tumor in the lower pole of the right kidney. Macroscopically, the entire tumor was sized 8x8x7 cm. Histologically, it was made up of ribbon-line or trabecular patterns of tumor cells. Occasional adenomatoid and cystic structures were present. The tumor cell nuclei were round or oval, with no irregularities and fine lumpy chromatin. The mitotic count was < 1 /10HPF and the proliferation marker Ki-67 was < 1 % of tumor cells. Immunohistochemically, the tumor cells were positive with antibodies against chromogranin A, synaptophysin, CD56 (focally), cytokeratins AE1-AE3 (focally), vimentin (most cells), glucagon (focally), and pancreatic polypeptide (PP; focally). Antibodies against serotonin, somatostatin, gastrin, vasoactive intestinal polypeptide (VIP) and calcitonin did not react with the tumor. The results of biochemical markers (5-HIAA, vanillylmandelic acid and NSE) did not correlate with development or treatment of the tumor., Conclusions: Primary neuroendocrine carcinoma of the kidney was diagnosed both histologically and immunohistochemically. The patient was clinically investigated using CT and OctreoScan scintigraphy. Within two years from nephrectomy, metastases were found in the right humerus and retrocaval lymph nodes. The metastatic lesions were surgically removed. Currently, the patient's condition is good, with no tumor progression detected.

IgM is the first antibody produced during the humoral immune response. Despite its fundamental role in the immune system, IgM is structurally only poorly described. In this work we used X-ray crystallography and NMR spectroscopy to determine the atomic structures of the constant IgM Fc domains (Cµ2, Cµ3, and Cµ4) and to address their roles in IgM oligomerization. Although the isolated domains share the typical Ig fold, they differ substantially in dimerization properties and quaternary contacts. Unexpectedly, the Cµ4 domain and its C-terminal tail piece are responsible and sufficient for the specific polymerization of Cµ4 dimers into covalently linked hexamers of dimers. Based on small angle X-ray scattering data, we present a model of the ring-shaped Cµ4 structure, which reveals the principles of IgM oligomerization.

Oxidant-mediated antibacterial response systems are broadly used to control bacterial proliferation. Hypochlorite (HOCl) is an important component of the innate immune system produced in neutrophils and specific epithelia. Its antimicrobial activity is due to damaging cellular macromolecules. Little is known about how bacteria escape HOCl-inflicted damage. Recently, the transcription factor YjiE was identified that specifically protects Escherichia coli from HOCl killing. According to its function, YjiE is now renamed HypT (hypochlorite-responsive transcription factor). Here we unravel that HypT is activated by methionine oxidation to methionine sulfoxide. Interestingly, so far only inactivation of cellular proteins by methionine oxidation has been reported. Mutational analysis revealed three methionines that are essential to confer HOCl resistance. Their simultaneous substitution by glutamine, mimicking the methionine sulfoxide state, increased the viability of E. coli cells upon HOCl stress. Triple glutamine substitution generates a constitutively active HypT that regulates target genes independently of HOCl stress and permanently down-regulates intracellular iron levels. Inactivation of HypT depends on the methionine sulfoxide reductases A/B. Thus, microbial protection mechanisms have evolved along the evolution of antimicrobial control systems, allowing bacteria to survive within the host environment.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is a rare condition affecting mostly women in the fifth and sixth decades of life. Here we present a case of its accidental finding in the lung parenchyma of a 56-year-old non-smoker female. In the periphery of the right middle lobe, linear and nodular proliferations were detected in the wall of the small bronchi and terminal and respiratory bronchioles. Under the pleura, several tumorlets were located. Immunohistologically, neuroendocrine cells were positive with antibodies against chromogranin A, synaptophysin, CD56, serotonin (weak positivity of some cells only), calcitonin, GRP/bombesin, cytokeratin 7 and TTF-1.

Large cell neuroendocrine carcinoma of the urinary bladder is rare. In the last five years, we have had the opportunity to see this type of cancer in an 88-year-old and in a 66-year-old males. In both cases, transurethral resection of carcinoma of the bladder was carried out. In the first case, urothelial carcinoma was detected and deeper in the bladder wall, large cell neuroendocrine carcinoma structures were found. In the second case, the bladder was only infiltrated with large cell neuroendocrine carcinoma. Both tumors expressed NSE, CD56 and synaptophysin. Other markers, such as those against calcitonin, chromogranin, PP, VIP, serotonin, gastrin, glucagon and somatostatin did not react with the tumor. In the first case, no tumor dissemination was found; in the second case, clinical methods confirmed dissemination into the liver, left adrenal gland, spleen and paracaval lymph nodes. Given his age, the first patient only received symptomatic therapy. The other patient underwent chemotherapy and his condition is stable. Paraneoplastic manifestations of the tumors were not clinically found. Histogenetic origin of neuroendocrine tumors is not fully clarified. In some cases, tumor development is thought to be associated with Brunns nests, cystitis cystica and urothelial carcinoma stem cells.

The transition of microtubules (MTs) from an assembled to a disassembled state plays an essential role in several cellular functions. While MT dynamics are often linked to those of actin filaments, little is known about whether intermediate filaments (IFs) have an influence on MT dynamics. We show here that plectin 1c (P1c), one of the multiple isoforms of the IF-associated cytolinker protein plectin, acts as an MT destabilizer. We found that MTs in P1c-deficient (P1c(-/-)) keratinocytes are more resistant toward nocodazole-induced disassembly and display increased acetylation. In addition, live imaging of MTs in P1c(-/-), as well as in plectin-null, cells revealed decreased MT dynamics. Increased MT stability due to P1c deficiency led to changes in cell shape, increased velocity but loss of directionality of migration, smaller-sized focal adhesions, higher glucose uptake, and mitotic spindle aberrations combined with reduced growth rates of cells. On the basis of ex vivo and in vitro experimental approaches, we suggest a mechanism for MT destabilization in which isoform-specific binding of P1c to MTs antagonizes the MT-stabilizing and assembly-promoting function of MT-associated proteins through an inhibitory function exerted by plectin's SH3 domain. Our results open new perspectives on cytolinker-coordinated IF-MT interaction and its physiological significance.

The tumor suppressor protein p53 is often referred to as the guardian of the genome. In the past, controversial findings have been presented for the role of the C-terminal regulatory domain (RD) of p53 as both a negative regulator and a positive regulator of p53 activity. However, the underlying mechanism remained enigmatic. To understand the function of the RD and of a dominant phosphorylation site within the RD, we analyzed p53 variants in vivo and in vitro. Our experiments revealed, surprisingly, that the p53 RD of one subunit interacts with the DNA binding domain of an adjacent subunit in the tetramer. This leads to the formation of intersubunit contacts that stabilize the tetrameric state of p53 and enhance its transcriptional activity in a cooperative manner. These effects are further modulated by phosphorylation of a conserved serine within the RD., (Copyright © 2012. Published by Elsevier Ltd.)

Influence of gravity forces on the regulation of protein expression by healthy and malignant thyroid cells was studied with the aim to identify protein interactions. Western blot analyses of a limited number of proteins suggested a time-dependent regulation of protein expression by simulated microgravity. After applying free flow isoelectric focusing and mass spectrometry to search for differently expressed proteins by thyroid cells exposed to simulated microgravity for three days, a considerable number of candidates for gravi-sensitive proteins were detected. In order to show how proteins sensitive to microgravity could directly influence other proteins, we investigated all polypeptide chains identified with Mascot scores above 100, looking for groups of interacting proteins. Hence, UniProtKB entry numbers of all detected proteins were entered into the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and processed. The program indicated that we had detected various groups of interacting proteins in each of the three cell lines studied. The major groups of interacting proteins play a role in pathways of carbohydrate and protein metabolism, regulation of cell growth and cell membrane structuring. Analyzing these groups, networks of interaction could be established which show how a punctual influence of simulated microgravity may propagate via various members of interaction chains.

The detection of metal particles in the pathologically altered tissues (eg. in inflammatory lesions or tumors) led to the idea that they might be associated with emergence of some idiopathic diseases. To understand the etiopathogenesis of diseases associated with the presence of nanoparticles in the tissue there is a new area of pathology - nanopathology. Numerous studies have shown that nanoparticles can enter the human body through inhalation or ingestion. Through the pulmonary alveoli, skin and intestinal mucosa, the nanoparticles may reach the blood and lymphatic system, which subsequently distributes them to other target organs. Epithelial surfaces of conjunctiva and skin represent another potential way of penetration of nanoparticles into the body. There is a number of studies, which described the adverse effects of ultrafine particles on respiratory and cardiovascular system. Recent studies have also shown that some nanoparticles are able to pass through the pores of the nuclear membrane, where they may pose a risk of damage to cells and genetic information and they are also potentially capable to cross the placental and hematoencephalic barriers. Further, their role in the induction of oxidative stress is significant in relation to the mutagenesis. Scanning electron microscopy with energy disperse spectroscopy (SEM-EDS) represents a suitable tool for identification of metal-based particles in tissues and body fluids. Importance of nanopathology can be seen in the elucidation of the etiopathogenesis of many diseases, not only of respiratory and cardiovascular systems, but also of many other organ systems.

Background: Endothelial cells (EC) cultured under altered gravity conditions show a cytoskeletal disorganization and differential gene expression (short-term effects), as well as apoptosis in adherently growing EC or formation of tubular 3D structures (long-term effects)., Methods: Investigating short-term effects of real microgravity, we exposed EC to parabolic flight maneuvers and analysed them on both protein and transcriptional level. The effects of hypergravity and vibration were studied separately., Results: Pan-actin and tubulin proteins were elevated by vibration and down-regulated by hypergravity. β-Actin was reduced by vibration. Moesin protein was reduced by both vibration and hypergravity, ezrin potein was strongly elevated under vibration. Gene expression of ACTB, CCND1, CDC6, CDKN1A, VEGFA, FLK-1, EZR, ITBG1, OPN, CASP3, CASP8, ANXA2, and BIRC5 was reduced under vibration. With the exception of CCNA2, CCND1, MSN, RDX, OPN, BIRC5, and ACTB all investigated genes were downregulated by hypergravity. After one parabola (P) CCNA2, CCND1, CDC6, CDKN1A, EZR, MSN, OPN, VEGFA, CASP3, CASP8, ANXA1, ANXA2, and BIRC5 were up-, while FLK1 was downregulated. EZR, MSN, OPN, ANXA2, and BIRC5 were upregulated after 31P., Conclusions: Genes of the cytoskeleton, angiogenesis, extracellular matrix, apoptosis, and cell cycle regulation were affected by parabolic flight maneuvers. We show that the microgravity stimulus is stronger than hypergravity/vibration., (Copyright © 2013 S. Karger AG, Basel.)

Background/aims: Thyroid cancer accounts for about 1% of all cancer cases. Multikinase inhibitors like sunitinib (S) have a promising potential in thyroid cancer therapy. Therefore, the principal aim of this study was to investigate the impact of sunitinib on the secretion of cytokines of follicular thyroid cancer cells., Method: The effects of irradiation (R), S, and their combination (R+S) on cytokine secretion by the human thyroid cancer cell lines ML-1 and CGTH W-1 were evaluated after two (d2) and four days (d4) of treatment., Results: Multi-Analyte Profiling of cytokine release showed a decrease after S treatment (CGTH W-1: IFN-γ, IL-4, IL-8 d2, MIP-1a, MMP-2, TNF-α and TNF-β; ML-1: IFN-γ, IL-4, IL-6, IL-7, IL-8; MIP-1α, MMP-2, MCP-1, TNF-α and TNF-β). R elevated significantly the release of cytokines (exception ML-1: MCP-1, MMP-2; CGTH W-1: IL-4, TNF-β). In contrast, R+S treatment resulted in a reduction of IFN-γ, IL-4, and MMP-2 in both cell lines. IL-6, IL-8 and MCP-1 proteins in the supernatant correlated with the data obtained by quantitative RT-PCR. VEGFD mRNAs were significantly elevated by R+S., Conclusion: A target-based therapy with R+S changed VEGFD, IL-6 and IL-8 in follicular thyroid cancer cells. These in vitro-experiments suggest IL-6, IL-8, VEGFD and TNF-α as interesting biomarkers to be investigated in vivo. Different reactions of the cell lines under equal treatment might be due to their different origin and characteristics., (Copyright © 2013 S. Karger AG, Basel.)

Organic amendments often represent a source of trace metals (TMs) in soils, which may partly leach into the groundwater. The objectives of this study were (1) to validate Hydrus-2D for modeling the transport of Zn and Cu in an Alfisol amended with pig slurry (PS) by comparing numerical simulations and experimental field data, and (2) to model the next 50 years of TM movements under scenarios of suspended or continued PS amendments. First, between 2000 and 2008, we collected detailed Zn and Cu data from a soil profile in Santa Maria, Brazil. Two hypotheses about Zn and Cu reactivity with the solid phase were tested, considering physical, hydraulic, and chemical characteristics of six soil layers. Using a two-site sorption model with a sorption kinetic rate adjusted based on laboratory EDTA extractions, Hydrus simulations of the vertical TM transport were found to satisfactorily describe the soil Zn and Cu concentration profiles. Second, the long-term fate of Zn and Cu in the soil was assessed using the validated parameterized model. Numerical simulations showed that Zn and Cu did not present risks for groundwater pollution. However, future Cu accumulation in the surface soil layer would exceed the Brazilian threshold for agricultural soils., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This study focused on the effects induced by a random positioning machine (RPM) on FTC-133 thyroid cancer cells and evaluated signaling elements involved in 3-dimensional multicellular tumor spheroid (MCTS) formation. The cells were cultured on the RPM, a device developed to simulate microgravity, and under static 1-g conditions. After 24 h on the RPM, MCTSs swimming in culture supernatants were found, in addition to growth of adherent (AD) cells. Cells grown on the RPM showed higher levels of NF-κB p65 protein and apoptosis than 1-g controls, a result also found earlier in endothelial cells. Employing microarray analysis, we found 487 significantly regulated transcripts belonging not only to the apoptosis pathway but also to other biological processes. Selected transcripts were analyzed with quantitative real-time PCR using the same samples. Compared with 1-g IL-6, IL-8, CD44, and OPN were significantly up-regulated in AD cells but not in MCTSs, while ERK1/2, CAV2, TLN1, and CTGF were significantly down-regulated in AD cells. Simultaneously, the expression of ERK2, IL-6, CAV2, TLN1, and CTGF was reduced in MCTSs. IL-6 protein expression and secretion mirrored its gene expression. Thus, we concluded that the signaling elements IL-6, IL-8, OPN, TLN1, and CTGF are involved with NF-κB p65 in RPM-dependent thyroid carcinoma cell spheroid formation.

Illicit drug use continues to be an important public health and safety concern in Europe. Production, trafficking and dealing in illicit drugs constitute important criminal justice challenges in themselves, and are associated with other criminal activities. The 2005-2012 EU Drugs Strategy (as with previous strategies) was developed to complement and add value to national strategies and approaches while respecting the principles of subsidiarity and proportionality set out in the EU Treaties. The main rationale for its development was that while drugs problems vary across Member States, and are experienced at the local and national level, they are "a global issue that needs to be addressed in a transnational context." RAND Europe undertook an independent evaluation of the current Strategy and its Action Plans, addressing four research objectives: (1) to assess barriers and facilitators to the implementation of objectives and priorities at EU and Member State level, (2) to assess the relevance and influence of the Strategy with respect to national drugs policy and legislation, (3) to assess possible impact on the drugs situation in the EU, and (4) to identify key aspects and recommendations for future EU Drugs Strategies.