An overview of angiogenesis in bladder cancer

Purpose of the review: Angiogenesis plays a key role in bladder cancer (BC) pathogenesis. In the last two decades, increasing number of publications depicting a multitude of novel angiogenic molecules and pathways have emerged. The growing complexity necessitates evaluation of the breadth of current knowledge to highlight key findings and guide future research. Recent findings: Angiogenesis is a dynamic biologic process that is inherently difficult to assess. Clinical assessment of angiogenesis in BCs is advancing with the integration of image analysis systems and dynamic contrast-enhanced and magnetic resonance imaging (DCE-MRI). Tumour associated macrophages (TAMs) significantly influence the angiogenic process and further research is needed to assess their potential as therapeutic targets. A rapidly growing list of non-coding RNAs affect angiogenesis in BCs, partly through modulation of vascular endothelial growth factor (VEGF) activity. Vascular mimicry (VM) has been repeatedly associated with increased tumour aggressiveness in BCs. Standardised assays are needed for appropriate identification and quantification of VM channels. Summary: This article demonstrates the dynamic and complex nature of the angiogenic process and asserts the need for further studies to deepen our understanding

Beneficial effects of voluntary over forced exercise on skeletal muscle structure and myokines’ expression

Background: Myokines, a group of small proteins — mainly cytokines, are released by myocytes during muscular contraction and proved to have many biological effects locally or at systemic levels. The main objective was to study the morphological alterations and myokines expression in rat gastrocnemius muscle following forced compared to voluntary muscle contraction. Materials and methods: Thirty-six adult male Wistar rats were divided into three groups: control, voluntary exercise and forced swimming regimen. The experiment last for 3 weeks. The weight of rats and serum corticosterone levels were recorded. The gastrocnemius muscle samples were processed for histological and immunohistochemical study of different myokines. Results: The mean weight of rats showed no statistical difference between groups. Corticosterone level significantly increased after forced exercise. Voluntary exercise muscle fibres appeared hypertrophied with prominent transverse banding and dominating satellite cells. Forced exercise muscle showed atrophied widely spaced muscle fibres and inflammatory cell infiltrate. Voluntary exercise significantly increased optic density of interleukin 6, macrophage inhibitory and brain derived neurotrophic factors, whereas the forced exercise group showed significant decrease in their optic densities. The optic density of vascular endothelial growth factor significantly decreased in the forced exercise group. Forced exercise could be harmful to the skeletal muscle fibres and it decreases the secretion of important myokines. Further, forced exercise significantly increases the serum corticosterone level. Conclusions: The use of exercise for the attainment of healthy life style or in psycho- or neuro-therapy should follow a thoroughly studied programme for welfare of human health

Morphometric and immunohistochemical study of angiogenic marker expressions in invasive ductal carcinomas of the human breast

Breast cancer is the leading cause of cancer deaths among women. Results from experimental studies suggest that tumour progression and metastasis in breast cancer are angiogenesis dependant. The College of American Pathologists has stated that further study of quantification of tumour angiogenesis is still required to demonstrate its prognostic value in breast cancer. In this study, not only the microvascular density (MVD), but also the vascular area ratio (VAR), and the vascular count in different grades of invasive ductal breast carcinoma were assessed using a pan-endothelial marker, CD34, and monoclonal antibody to CD105, by employing computer assisted morphometric measurements. In addition, quantitative expression of vascular endothelial growth factor (VEGF) was detected. Correlation of the vascular parameters and VEGF expression with the different grades of invasive ductal breast carcinoma was clarified. Immunohistochemical staining for the CD105, CD34, and VEGF antibodies were performed in 25 patients with invasive ductal carcinoma in King Fahd Hospital, Saudi Arabia. Normal breast tissue samples comprised 15 specimens detected at the safety margin of the malignant breast cases were collected. Positive CD34 stained blood-vessel endothelial cells were observed in all normal breast tissues. In contrast, CD105 and VEGF expression were not expressed in the normal breast ducts and lobules. Widespread staining for CD34, to a lesser extent CD105, and VEGF expression were seen in all tumour specimens with different grades. Significant differences in the vascular parameters, stained with antiCD34, were observed between normal breast tissues and invasive ductal carcinoma. In addition, the vascular parameters stained with antiCD34 and antiCD105, and the percentage of VEGF expression in the three grades of invasive ductal carcinomas showed significant differences with positive correlations. In conclusion, MVD as well as VAR are considered to reflect the final result of the tumour angiogenesis cascade. In addition, VEGF expression was found to be a useful angiogenic marker. However, few cases were VEGF negatively stained. Thus, the expression of MVD, VAR, and to a lesser extent VEGF might be reference predictors for the biological behaviour and prognosis of breast carcinoma

A Probabilistic Performance Assessment Model for General Corrosion of Alloy 22 for High Level Nuclear Waste Disposal Container

Alloy 22 (UNS N06022) is the candidate material for the corrosion barrier of the double-wall waste package (WP) for the disposal of high-Gel nuclear waste at the proposed Yucca Mountain repository. A probabilistic temperature-dependent general corrosion model for the WP outer barrier (WPOB) was developed based on the 5-year weight-loss measurements of Alloy 22 crevice samples. The 5-year corrosion rate distribution is represented by a Weibull distribution, with scale factors = 8.88, shape factor b = 1.62, and location factor l = 0. The temperature-dependence of the general corrosion rate was modeled using an Arrhenius relation. An activation energy of 25.91 {+-} 2.46 kJ/mol was determined from the corrosion rates obtained from the short-term polarization resistance data for Alloy 22 specimens tested for a wide range of sample configurations, metallurgical conditions, and exposure conditions (temperature and water chemistry). Analysis of the data from the current study and the literature indicates that the activation energies of general corrosion rate of highly corrosion resistant Ni-Cr-Mo alloys including Alloy 22 are similar and do not change significantly, as the general corrosion rate decreases with the exposure time. The 5-year corrosion rates were conservatively selected for extrapolation over the repository time scale. Because of very low general corrosion rates of the WPOB for the conditions expected in the proposed repository, the WP performance will not be limited by general corrosion for the repository regulatory time period. The current conservative approach for the constant (time-independent) general corrosion rate at a given temperature provides an additional confidence for the general corrosion model

An approach for simulating regional migration patterns

In this paper, GERTS III is presented as a possible approach for simulating regional migration patterns. Fourteen years of aggregate Canadian census data were compiled and a mathematical model was constructed to describe the patterns of inter-regional migration viewed as a discrete time Markov process. A GERTS III network was developed to analyze and describe this process. Measures of population mobility, degree of mobility and retention were derived. The implications for policy makers are highlighted.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24487/1/0000763.pd

Gas Centrifuge Enrichment Plant Safeguards System Modeling

The U.S. Department of Energy (DOE) is interested in developing tools and methods for potential U.S. use in designing and evaluating safeguards systems used in enrichment facilities. This research focuses on analyzing the effectiveness of the safeguards in protecting against the range of safeguards concerns for enrichment plants, including diversion of attractive material and unauthorized modes of use. We developed an Extend simulation model for a generic medium-sized centrifuge enrichment plant. We modeled the material flow in normal operation, plant operational upset modes, and selected diversion scenarios, for selected safeguards systems. Simulation modeling is used to analyze both authorized and unauthorized use of a plant and the flow of safeguards information. Simulation tracks the movement of materials and isotopes, identifies the signatures of unauthorized use, tracks the flow and compilation of safeguards data, and evaluates the effectiveness of the safeguards system in detecting misuse signatures. The simulation model developed could be of use to the International Atomic Energy Agency IAEA, enabling the IAEA to observe and draw conclusions that uranium enrichment facilities are being used only within authorized limits for peaceful uses of nuclear energy. It will evaluate improved approaches to nonproliferation concerns, facilitating deployment of enhanced and cost-effective safeguards systems for an important part of the nuclear power fuel cycle

Modeling Efforts to Aid in the Determination of Process Enrichment Levels for Identifying Potential Material Diversion

Efforts have been under way at Lawrence Livermore National Laboratory (LLNL) to develop detailed analytical models that simulate enrichment and conversion facilities for the purpose of aiding in the detection of material diversion as part of an overall safeguards strategy. These models could be used to confirm proper accountability of the nuclear materials at facilities worldwide. Operation of an enrichment process for manufacturing commercial reactor fuel presents proliferation concerns including both diversion and the potential for further enrichment to make weapons grade material. While inspections of foreign reprocessing facilities by the International Atomic Energy Agency (IAEA) are meant to ensure that such diversion is not occurring, it must be verified that such diversion is not taking place through both examination of the facility and taking specific measurements such as the radiation fields outside of various process lines. Our current effort is developing algorithms that would be incorporated into the current process models that would provide both neutron and gamma radiation fields outside any process line for the purpose of to determining the most effective locations for placing in-plant monitoring equipment. These algorithms, while providing dose and spectral information, could also be designed to provide detector responses that could be physically measured at various points on the process line. Such information could be used to optimize detector locations in support of real-time on-site monitoring to determine the enrichment levels within a process stream. The results of parametric analyses to establish expected variations for several different process streams and configurations are presented. Based upon these results, the capability of a sodium iodide (NaI(Tl)), high-purity germanium (HPGe), or neutron detection system is being investigated from the standpoint of their viability in quantitatively measuring and discerning the enrichment and potential throughput variations thereof. The benefits and issues associated with both passive and active interrogation measurement techniques are also discussed

Modeling Efforts to Aid in the Prediction of Process Enrichment Levels with the Intent of Identifying Potential Material Diversion

As part of an ongoing effort at Lawrence Livermore National Laboratory (LLNL) to enhance analytical models that simulate enrichment and conversion facilities, efforts are underway to develop routines to estimate the total gamma-ray flux and that of specific lines around process piping containing UF{sub 6}. The intent of the simulation modeling effort is to aid in the identification of possible areas where material diversion could occur, as input to an overall safeguards strategy. The operation of an enrichment facility for the production of low enriched uranium (LEU) presents certain proliferation concerns, including both the possibility of diversion of LEU and the potential for producing material enriched to higher-than-declared, weapons-usable levels. Safeguards applied by the International Atomic Energy Agency (IAEA) are designed to provide assurance against diversion or misuse. Among the measures being considered for use is the measurement of radiation fields at various locations in the cascade hall. Our prior efforts in this area have focused on developing a model to predict neutron fields and how they would change during diversion of misuse. The neutron models indicated that while neutron detection useful in monitoring feed and product containers, it was not useful for monitoring process lines. Our current effort is aimed at developing algorithms that provide estimates of the gamma radiation field outside any process line for the purpose of determining the most effective locations for placing in-plant gamma-monitoring equipment. These algorithms could also be modified to provide both dose and spectral information and, ultimately, detector responses that could be physically measured at various points on the process line. Such information could be used to optimize detector locations in support of real-time on-site monitoring to determine the enrichment levels within a process stream. The results of parametric analyses to establish expected variations for several different process streams and configurations are presented. The benefits and issues associated with both passive and active interrogation measurement techniques are also being explored

LISSAT Analysis of a Generic Centrifuge Enrichment Plant

The U.S. Department of Energy (DOE) is interested in developing tools and methods for use in designing and evaluating safeguards systems for current and future plants in the nuclear power fuel cycle. The DOE is engaging several DOE National Laboratories in efforts applied to safeguards for chemical conversion plants and gaseous centrifuge enrichment plants. As part of the development, Lawrence Livermore National Laboratory has developed an integrated safeguards system analysis tool (LISSAT). This tool provides modeling and analysis of facility and safeguards operations, generation of diversion paths, and evaluation of safeguards system effectiveness. The constituent elements of diversion scenarios, including material extraction and concealment measures, are structured using directed graphs (digraphs) and fault trees. Statistical analysis evaluates the effectiveness of measurement verification plans and randomly timed inspections. Time domain simulations analyze significant scenarios, especially those involving alternate time ordering of events or issues of timeliness. Such simulations can provide additional information to the fault tree analysis and can help identify the range of normal operations and, by extension, identify additional plant operational signatures of diversions. LISSAT analyses can be used to compare the diversion-detection probabilities for individual safeguards technologies and to inform overall strategy implementations for present and future plants. Additionally, LISSAT can be the basis for a rigorous cost-effectiveness analysis of safeguards and design options. This paper will describe the results of a LISSAT analysis of a generic centrifuge enrichment plant. The paper will describe the diversion scenarios analyzed and the effectiveness of various safeguards systems alternatives

Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study

Acute heart failure (AHF) is one of the most common diseases in old age that can lead to mortality. Systemic hypoperfusion is associated with hepatic ischemia–reperfusion injury, which may be irreversible. Ischemic hepatitis due to AHF has been linked to the pathogenesis of liver damage. In the present study, we extensively investigated the role of mitochondrial dynamics-related proteins and their epigenetic regulation in ischemic liver injury following AHF and explored the possible hepatoprotective role of carvedilol. The biochemical analysis revealed that the ischemic liver injury following AHF significantly elevated the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes, the level of total and direct bilirubin, and the expression of hepatic mitogen-activated protein kinase (MAPK), dynamin-1-like protein (DNM1L), and hepatic miRNA-17. At the same time, it significantly reduced the serum albumin level, the activity of hepatic superoxide dismutase (SOD), and the expression of mitochondrial peroxisome proliferator-activated receptor-1α (PGC-1α), and mitofusin 2 (Mtf2). The histological examination of the liver tissue revealed degenerated hepatocytes. Interestingly, administration of carvedilol either prior to or after isoprenaline-induced AHF significantly improved the liver function and reversed the deterioration effect of AHF-induced ischemic hepatitis, as demonstrated by biochemical, immunohistochemical, and histological analysis. Our results indicated that the hepatoprotective effect of carvedilol in ameliorating hepatic ischemic damage could be attributed to its ability to target the mitochondrial dynamics-related proteins (Mtf2, DNM1L and PGC-1α), but also their epigenetic regulator miRNA-17. To further explore the mode of action of carvedilol, we have investigated, in silico, the ability of carvedilol to target dynamin-1-like protein and mitochondrial dynamics protein (MID51). Our results revealed that carvedilol has a high binding affinity (−14.83 kcal/mol) toward the binding pocket of DNM1L protein. In conclusion, our study highlights the hepatoprotective pharmacological application of carvedilol to attenuate ischemic hepatitis associated with AHF.Faculty of Medicine, and Faculty of Science, Ain Shams UniversityPrincess Nourah bint Abdulrahman Universit