Role and Function of c-Jun Protein Complex in Cancer Cell Behavior

Transcription factors play a crucial role in the regulation of cell behavior by modulating gene expression profiles. Previous studies have described a dual role for the AP-1 family transcription factor c-Jun in the regulation of cellular fate. In various cell types weak and transient activations of c-Jun N-terminal kinase (JNK) and c-Jun appear to contribute to proliferation and survival, whereas strong and prolonged activation of JNK and c-Jun result in apoptosis. These opposite roles played by c-Jun are cell type specific and the molecular mechanisms defining these antonymous c-Jun-mediated responses remain incompletely understood. c-Jun activity in transformed cells is regulated by signalling cascades downstream of oncoproteins such as Ras and Raf. In addition, the pro-proliferative role and the survival promoting function for c-Jun has been described in various cancer models. Furthermore, c-Jun was described to be overexpressed in different cancer types. However, the molecular mechanisms by which c-Jun exerts these oncogenic functions are not all clearly established. Therefore it is of primary interest to further identify molecular mechanisms and functions for c-Jun in cancer. Regulation of gene expression is tightly dependent on accurate protein-protein interactions. Therefore, co-factors for c-Jun may define the functions for c-Jun in cancer. Identification of protein-protein interactions promoting cancer may provide novel possibilities for cancer treatment. In this study, we show that DNA topoisomerase I (TopoI) is a transcriptional co-factor for c-Jun. Moreover, c-Jun and TopoI together promote expression of epidermal growth factor receptor (EGFR) in cancer cells. We also show that the clinically used TopoI inhibitor topotecan reduces EGFR expression. Importantly, the effect of TopoI on EGFR transcription was shown to depend on c-Jun as Jun-/- cells or cells treated with JNK inhibitor SP600125 are resistant to topotecan treatment both in regulation of EGFR expression and cell proliferation. Moreover, c-Jun regulates the nucleolar localization and the function of the ribonucleic acid (RNA) helicase DDX21, a previously identified member of c-Jun protein complex. In addition, c-Jun stimulates rRNA processing by supporting DDX21 rRNA binding. Finally, this study characterizes a DDX21 dependent expression of cyclin dependent kinase (Cdk) 6, a correlation of DDX21 expression with prostate cancer progression and a substrate binding dependency of DDX21 nucleolar localization in prostate cancer cells. Taken together, the results of this study validate the c-Jun-TopoI interaction and precise the c-Jun-DDX21 interaction. Moreover, these results show the importance for protein-protein interaction in the regulation of their cellular functions in cancer cell behavior. Finally, the results presented here disclose new exciting therapeutic opportunities for cancer treatment.

The determination of the stoichiometry of the mixed complex of vanadium with hydrogen peroxide and with 4-(2-Pyridilazo) Resorcinol

The present study reports details of the stoichiometric characterization of the mixed complex system, V(H2O2)PAR, formed when vanadium adequately reacts with hydrogen peroxide and with 4-(2-Pyridilazo)Resorcinol. Also the presence of polynuclear species was investigated in order to elucidate about unambiguous assignment of the molar absorptivity, stability constant and composition of the complex. Two mathematical treatments methods of the experimental results were employed. From the results it can be concluded that this system corresponds to a mononuclear complex with 1:1:1 stoichiometry.

Tuberous sclerosis complex with oral manifestations: A case report and literature review

Introduction: Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome produced by a number of genetic mutations. The disease is characterized by the development of benign tumors affecting different body systems. The most common oral manifestations of TSC are fibromas, gingival hyperplasia and enamel hypoplasia. Clinical Case: A 35-year-old woman diagnosed with TSC presented with a reactive fibroma of considerable size and rapid growth in the region of the right lower third molar. Discussion: In the present case the association of TSC with dental malpositioning gave rise to a rapidly evolving reactive fibroma of considerable diameter. Few similar cases can be found in the literature. Patients with TSC present mutations of the TSC1 and TSC2 genes, which intervene in cell cycle regulation and are important for avoiding neoplastic processes. No studies have been found associating TSC with an increased risk of oral cancer, though it has been shown that the over-expression of TSC2 could exert an antitumor effect. Careful oral and dental hygiene, together with regular visits to the dentist, are needed for the prevention and early detection of any type of oral lesion. The renal, pulmonary and cardiac alterations often seen in TSC must be taken into account for the correct management of these patients.

Inclusion complex of the antiviral drug acyclovir with cyclodextrin in aqueous solution and in solid phase

Complexation between acyclovir (ACV), an antiviral drug used for the treatment of herpes simplex virus infection, and beta-cyclodextrin (beta-CD) was studied in solution and in solid states. Complexation in solution was evaluated using solubility studies and nuclear magnetic resonance spectroscopy (¹H-NMR). In the solid state, X-ray diffraction, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) and dissolution studies were used. Solubility studies suggested the existence of a 1:1 complex between ACV and beta-CD. ¹H-NMR spectroscopy studies showed that the complex formed occurs with a stoichiometry ratio of 1:1. Powder X-ray diffraction indicated that ACV exists in a semicrystalline state in the complexed form with beta-CD. DSC studies showed the existence of a complex of ACV with beta-CD. The TGA studies confirmed the DSC results of the complex. Solubility of ACV in solid complexes was studied by the dissolution method and it was found to be much more soluble than the uncomplexed drug.

Outer membrane vesicles from cold-adapted antarctic bacteria

Many Gram-negative, cold-adapted bacteria from the Antarctic environment produce large amounts of extracellular matter with potential biotechnological applications. Transmission electron microscopy (TEM) analysis after high-pressure freezing and freeze substitution (HPF-FS) showed that this extracellular matter is structurally complex, appearing around cells as a netlike mesh, and composed of an exopolymeric substance (EPS) containing large numbers of outer membrane vesicles (OMVs). Isolation, purification and protein profiling via 1D SDS-PAGE confirmed the outer membrane origin of these Antarctic bacteria OMVs. In an initial attempt to elucidate the role of OMVs in cold-adapted strains of Gram-negative bacteria, a proteomic analysis demonstrated that they were highly enriched in outer membrane proteins and periplasmic proteins associated with nutrient processing and transport, suggesting that the OMVs may be involved in nutrient sensing and bacterial survival. OMVs from Gram-negative bacteria are known to play a role in lateral DNA transfer, but the presence of DNA in these vesicles has remained difficult to explain. A structural study of Shewanella vesiculosa M7T using TEM and Cryo-TEM revealed that this Antarctic Gram-negative bacterium naturally releases conventional one-bilayer OMVs, together with a more complex type of OMV, previously undescribed, which on formation drags along inner membrane and cytoplasmic content and can therefore also entrap DNA.

$E_{1}$-Formality of complex algebraic varieties

Let $X$ be a smooth complex algebraic variety. Morgan showed that the rational homotopy type of $X$ is a formal consequence of the differential graded algebra defined by the first term $E_{1}(X,W)$ of its weight spectral sequence. In the present work, we generalize this result to arbitrary nilpotent complex algebraic varieties (possibly singular and/or non-compact) and to algebraic morphisms between them. In particular, our results generalize the formality theorem of Deligne, Griffiths, Morgan and Sullivan for morphisms of compact Kähler varieties, filling a gap in Morgan"s theory concerning functoriality over the rationals. As an application, we study the Hopf invariant of certain algebraic morphisms using intersection theory.

Weight filtration on the cohomology of complex analytic spaces

We extend Deligne's weight filtration to the integer cohomology of complex analytic spaces (endowed with an equivalence class of compactifications). In general, the weight filtration that we obtain is not part of a mixed Hodge structure. Our purely geometric proof is based on cubical descent for resolution of singularities and Poincaré-Verdier duality. Using similar techniques, we introduce the singularity filtration on the cohomology of compactificable analytic spaces. This is a new and natural analytic invariant which does not depend on the equivalence class of compactifications and is related to the weight filtration.

ESTRO-HERO survey: Radiotherapy staffing in the European countries: Final results from the ESTRO-HERO survey

Background: The ESTRO Health Economics in Radiation Oncology (HERO) project has the overall aim to develop a knowledge base of the provision of radiotherapy in Europe and build a model for health economic evaluation of radiation treatments at the European level. The first milestone was to assess the availability of radiotherapy resources within Europe. This paper presents the personnel data collected in the ESTRO HERO database. Materials and methods: An 84-item questionnaire was sent out to European countries, through their national scientific and professional radiotherapy societies. The current report includes a detailed analysis of radiotherapy staffing (questionnaire items 4760), analysed in relation to the annual number of treatment courses and the socio-economic status of the countries. The analysis was conducted between February and July 2014, and is based on validated responses from 24 of the 40 European countries defined by the European Cancer Observatory (ECO). Results: A large variation between countries was found for most parameters studied. Averages and ranges for personnel numbers per million inhabitants are 12.8 (2.530.9) for radiation oncologists, 7.6 (019.7) for medical physicists, 3.5 (012.6) for dosimetrists, 26.6 (1.978) for RTTs and 14.8 (0.461.0) for radiotherapy nurses. The combined average for physicists and dosimetrists is 9.8 per million inhabitants and 36.9 for RTT and nurses. Radiation oncologists on average treat 208.9 courses per year (range: 99.9348.8), physicists and dosimetrists conjointly treat 303.3 courses (range: 85757.7) and RTT and nurses 76.8 (range: 25.7156.8). In countries with higher GNI per capita, all personnel categories treat fewer courses per annum than in less affluent countries. This relationship is most evident for RTTs and nurses. Different clusters of countries can be distinguished on the basis of available personnel resources and socio-economic status. Conclusions: The average personnel figures in Europe are now consistent with, or even more favourable than the QUARTS recommendations, probably reflecting a combination of better availability as such, in parallel with the current use of more complex treatments than a decade ago. A considerable variation in available personnel and delivered courses per year however persists among the highest and lowest staffing levels. This not only reflects the variation in cancer incidence and socio-economic determinants, but also the stage in technology adoption along with treatment complexity and the different professional roles and responsibilities within each country. Our data underpin the need for accurate prediction models and long-term education and training programmes

Analysis of a Plant Complex Resistance Gene Locus Underlying Immune-Related Hybrid Incompatibility and Its Occurrence in Nature

Mechanisms underlying speciation in plants include detrimental (incompatible) genetic interactions between parental alleles that incur a fitness cost in hybrids. We reported on recessive hybrid incompatibility between an Arabidopsis thaliana strain from Poland, Landsberg erecta (Ler), and many Central Asian A. thaliana strains. The incompatible interaction is determined by a polymorphic cluster of Toll/interleukin-1 receptor-nucleotide binding-leucine rich repeat (TNL) RPP1 (Recognition of Peronospora parasitica1)-like genes in Ler and alleles of the receptor-like kinase Strubbelig Receptor Family 3 (SRF3) in Central Asian strains Kas-2 or Kond, causing temperature-dependent autoimmunity and loss of growth and reproductive fitness. Here, we genetically dissected the RPP1-like Ler locus to determine contributions of individual RPP1-like Ler (R1R8) genes to the incompatibility. In a neutral background, expression of most RPP1-like Ler genes, except R3, has no effect on growth or pathogen resistance. Incompatibility involves increased R3 expression and engineered R3 overexpression in a neutral background induces dwarfism and sterility. However, no individual RPP1-like Ler gene is sufficient for incompatibility between Ler and Kas-2 or Kond, suggesting that co-action of at least two RPP1-like members underlies this epistatic interaction. We find that the RPP1-like Ler haplotype is frequent and occurs with other Ler RPP1-like alleles in a local population in Gorzów Wielkopolski (Poland). Only Gorzów individuals carrying the RPP1-like Ler haplotype are incompatible with Kas-2 and Kond, whereas other RPP1-like alleles in the population are compatible. Therefore, the RPP1-like Ler haplotype has been maintained in genetically different individuals at a single site, allowing exploration of forces shaping the evolution of RPP1-like genes at local and regional population scales.

Fuzzy subgroups, algebraic and topological points of view and complex analysis

Fuzzy subsets and fuzzy subgroups are basic concepts in fuzzy mathematics. We shall concentrate on fuzzy subgroups dealing with some of their algebraic, topological and complex analytical properties. Explorations are theoretical belonging to pure mathematics. One of our ideas is to show how widely fuzzy subgroups can be used in mathematics, which brings out the wealth of this concept. In complex analysis we focus on Möbius transformations, combining them with fuzzy subgroups in the algebraic and topological sense. We also survey MV spaces with or without a link to fuzzy subgroups. Spectral space is known in MV algebra. We are interested in its topological properties in MV-semilinear space. Later on, we shall study MV algebras in connection with Riemann surfaces. In fact, the Riemann surface as a concept belongs to complex analysis. On the other hand, Möbius transformations form a part of the theory of Riemann surfaces. In general, this work gives a good understanding how it is possible to fit together different fields of mathematics.

Outer membrane vesicles from cold-adapted antarctic bacteria

Many Gram-negative, cold-adapted bacteria from the Antarctic environment produce large amounts of extracellular matter with potential biotechnological applications. Transmission electron microscopy (TEM) analysis after high-pressure freezing and freeze substitution (HPF-FS) showed that this extracellular matter is structurally complex, appearing around cells as a netlike mesh, and composed of an exopolymeric substance (EPS) containing large numbers of outer membrane vesicles (OMVs). Isolation, purification and protein profiling via 1D SDS-PAGE confirmed the outer membrane origin of these Antarctic bacteria OMVs. In an initial attempt to elucidate the role of OMVs in cold-adapted strains of Gram-negative bacteria, a proteomic analysis demonstrated that they were highly enriched in outer membrane proteins and periplasmic proteins associated with nutrient processing and transport, suggesting that the OMVs may be involved in nutrient sensing and bacterial survival. OMVs from Gram-negative bacteria are known to play a role in lateral DNA transfer, but the presence of DNA in these vesicles has remained difficult to explain. A structural study of Shewanella vesiculosa M7T using TEM and Cryo-TEM revealed that this Antarctic Gram-negative bacterium naturally releases conventional one-bilayer OMVs, together with a more complex type of OMV, previously undescribed, which on formation drags along inner membrane and cytoplasmic content and can therefore also entrap DNA.

DWI and complex brain network analysis predicts vascular cognitive impairment in spontaneous hypertensive rats undergoing executive function tests

The identification of biomarkers of vascular cognitive impairment is urgent for its early diagnosis. The aim of this study was to detect and monitor changes in brain structure and connectivity, and to correlate them with the decline in executive function. We examined the feasibility of early diagnostic magnetic resonance imaging (MRI) to predict cognitive impairment before onset in an animal model of chronic hypertension: Spontaneously Hypertensive Rats. Cognitive performance was tested in an operant conditioning paradigm that evaluated learning, memory, and behavioral flexibility skills. Behavioral tests were coupled with longitudinal diffusion weighted imaging acquired with 126 diffusion gradient directions and 0.3 mm(3) isometric resolution at 10, 14, 18, 22, 26, and 40 weeks after birth. Diffusion weighted imaging was analyzed in two different ways, by regional characterization of diffusion tensor imaging (DTI) indices, and by assessing changes in structural brain network organization based on Q-Ball tractography. Already at the first evaluated times, DTI scalar maps revealed significant differences in many regions, suggesting loss of integrity in white and gray matter of spontaneously hypertensive rats when compared to normotensive control rats. In addition, graph theory analysis of the structural brain network demonstrated a significant decrease of hierarchical modularity, global and local efficacy, with predictive value as shown by regional three-fold cross validation study. Moreover, these decreases were significantly correlated with the behavioral performance deficits observed at subsequent time points, suggesting that the diffusion weighted imaging and connectivity studies can unravel neuroimaging alterations even overt signs of cognitive impairment become apparent.

One, two, or many mechanisms? The brain's processing of complex words

The heated debate over whether there is only a single mechanism or two mechanisms for morphology has diverted valuable research energy away from the more critical questions about the neural computations involved in the comprehension and production of morphologically complex forms. Cognitive neuroscience data implicate many brain areas. All extant models, whether they rely on a connectionist network or espouse two mechanisms, are too underspecified to explain why more than a few brain areas differ in their activity during the processing of regular and irregular forms. No one doubts that the brain treats regular and irregular words differently, but brain data indicate that a simplistic account will not do. It is time for us to search for the critical factors free from theoretical blinders.

Phase diagram and complex patterns in the modeling of the bromate-oxalic acid-Ce-acetone oscillating reaction

Simulations have been carried out on the bromate - oxalic acid - Ce(IV) - acetone oscillating reaction, under flow conditions, using Field and Boyd's model (J. Phys. Chem. 1985, 89, 3707). Many different complex dynamic behaviors were found, including simple periodic oscillations, complex periodic oscillations, quasiperiodicity and chaos. Some of these complex oscillations can be understood as belonging to a Farey sequence. The many different behaviors were systematized in a phase diagram which shows that some regions of complex patterns were nested with one inside the other. The existence of almost all known dynamic behavior for this system allows the suggestion that it can be used as a model for some very complex phenomena that occur in biological systems.

Human disease and drug pharmacology, complex as real life

In the past decades drug discovery practice has escaped from the complexity of the formerly used phenotypic screening in animals to focus on assessing drug effects on isolated protein targets in the search for drugs that exclusively and potently hit one selected target, thought to be critical for a given disease, while not affecting at all any other target to avoid the occurrence of side-effects. However, reality does not conform to these expectations, and, conversely, this approach has been concurrent with increased attrition figures in late-stage clinical trials, precisely due to lack of efficacy and safety. In this context, a network biology perspective of human disease and treatment has burst into the drug discovery scenario to bring it back to the consideration of the complexity of living organisms and particularly of the (patho)physiological environment where protein targets are (mal)functioning and where drugs have to exert their restoring action. Under this perspective, it has been found that usually there is not one but several disease-causing genes and, therefore, not one but several relevant protein targets to be hit, which do not work on isolation but in a highly interconnected manner, and that most known drugs are inherently promiscuous. In this light, the rationale behind the currently prevailing single-target-based drug discovery approach might even seem a Utopia, while, conversely, the notion that the complexity of human disease must be tackled with complex polypharmacological therapeutic interventions constitutes a difficult-torefuse argument that is spurring the development of multitarget therapies.