Endometrial carcinoma: molecular alterations involved in tumor development and progression

In the western world, endometrial carcinoma (EC) is the most common cancer of the female genital tract. The annual incidence has been estimated at 10-20 per 100 000 women. Two clinicopathological variants are recognized: the estrogen related (type I, endometrioid) and the non-estrogen related (type II, non-endometrioid).The clinicopathological differences are paralleled by specific genetic alterations, with type I showing microsatellite instability and mutations in phosphatase and tensin homologue deleted on chromosome 70, PIK3CA, K-RAS and CTNNB1 (beta-catenin), and type II exhibiting TP53 mutations and chromosomal instability. Some non-endometrioid carcinomas probably arise from pre-existing endometrioid carcinomas as a result of tumor progression and, not surprisingly, some tumors exhibit combined or mixed features at the clinical, pathological and molecular levels. In EC, apoptosis resistance may have a role in tumor progression. Understanding pathogenesis at the molecular level is essential in identifying biomarkers for successful targeted therapies. In this review, the genetic changes of endometrial carcinogenesis are discussed in the light of the morphological features of the tumors and their precursors

Identification of sex hormone-binding globulin in the human hypothalamus

Gonadal steroids are known to influence hypothalamic functions through both genomic and non-genomic pathways. Sex hormone-binding globulin ( SHBG) may act by a non-genomic mechanism independent of classical steroid receptors. Here we describe the immunocytochemical mapping of SHBG-containing neurons and nerve fibers in the human hypothalamus and infundibulum. Mass spectrometry and Western blot analysis were also used to characterize the biochemical characteristics of SHBG in the hypothalamus and cerebrospinal fluid (CSF) of humans. SHBG-immunoreactive neurons were observed in the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis, paraventricular nucleus, arcuate nucleus, the perifornical region and the medial preoptic area in human brains. There were SHBG-immunoreactive axons in the median eminence and the infundibulum. A partial colocalization with oxytocin could be observed in the posterior pituitary lobe in consecutive semithin sections. We also found strong immunoreactivity for SHBG in epithelial cells of the choroid plexus and in a portion of the ependymal cells lining the third ventricle. Mass spectrometry showed that affinity-purified SHBG from the hypothalamus and choroid plexus is structurally similar to the SHBG identified in the CSF. The multiple localizations of SHBG suggest neurohypophyseal and neuroendocrine functions. The biochemical data suggest that CSF SHBG is of brain rather than blood origin. Copyright (c) 2005 S. Karger AG, Base

Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer

Background: About 20% of patients diagnosed with endometrial cancer (EC) are considered high-risk with unfavorable prognosis. In the framework of the European Network for Individualized Treatment in EC (ENITEC), we investigated the presence and phenotypic features of Circulating Tumor Cells (CTC) in high-risk EC patients. Methods: CTC isolation was carried out in peripheral blood samples from 34 patients, ranging from Grade 3 Stage IB to Stage IV carcinomas and recurrences, and 27 healthy controls using two methodologies. Samples were subjected to EpCAM-based immunoisolation using the CELLection™ Epithelial Enrich kit (Invitrogen, Dynal) followed by RTqPCR analysis. The phenotypic determinants of endometrial CTC in terms of pathogenesis, hormone receptor pathways, stem cell markers and epithelial to mesenchymal transition (EMT) drivers were asked. Kruskal-Wallis analysis followed by Dunn's post-test was used for comparisons between groups. Statistical significance was set at p < 0.05. Results: EpCAM-based immunoisolation positively detected CTC in high-risk endometrial cancer patients. CTC characterization indicated a remarkable plasticity phenotype defined by the expression of the EMT markers ETV5, NOTCH1, SNAI1, TGFB1, ZEB1 and ZEB2. In addition, the expression of ALDH and CD44 pointed to an association with stemness, while the expression of CTNNB1, STS, GDF15, RELA, RUNX1, BRAF and PIK3CA suggested potential therapeutic targets. We further recapitulated the EMT phenotype found in endometrial CTC through the up-regulation of ETV5 in an EC cell line, and validated in an animal model of systemic dissemination the propensity of these CTC in the accomplishment of metastasis. Conclusions: Our results associate the presence of CTC with high-risk EC. Gene-expression profiling characterized a CTC-plasticity phenotype with stemness and EMT features. We finally recapitulated this CTC-phenotype by over-expressing ETV5 in the EC cell line Hec1A and demonstrated an advantage in the promotion of metastasis in an in vivo mouse model of CTC dissemination and homing

Main Results of Phase IV BEMUSE Project: Simulation of LBLOCA in an NPP

Phase IV of BEMUSE Program is a necessary step for a subsequent uncertainty analysis. It includes the simulation of the reference scenario and a sensitivity study. The scenario is a LBLOCA and the reference plant is Zion 1 NPP, a 4 loop PWR unit. Thirteen participants coming from ten different countries have taken part in the exercise. The BEMUSE (Best Estimate Methods plus Uncertainty and Sensitivity Evaluation) Programhas been promoted by theWorking Group on AccidentManagement and Analysis (WGAMA) and endorsed by the Committee on the Safety of Nuclear Installations (CSNI). The paper presents the results of the calculations performed by participants and emphasizes its usefulness for future uncertainty evaluation, to be performed in next phase. The objectives of the activity are basically to simulate the LBLOCA reproducing the phenomena associated to the scenario and also to build a common, well-known, basis for the future comparison of uncertainty evaluation results among different methodologies and codes. The sensitivity calculations performed by participants are also presented. They allow studying the influence of different parameters such as material properties or initial and boundary conditions, upon the behaviour of the most relevant parameters related to the scenario

PREMIUM, a benchmark on the quantification of the uncertainty of the physical models in the system thermal-hydraulic codes: methodologies and data review

The objective of the Post-BEMUSE Reflood Model Input Uncertainty Methods (PREMIUM) benchmark is to progress on the issue of the quantification of the uncertainty of the physical models in system thermalhydraulic codes by considering a concrete case: the physical models involved in the prediction of core reflooding. The present document was initially conceived as a final report for the Phase I “Introduction and Methodology Review” of the PREMIUM benchmark. The objective of Phase I is to refine the definition of the benchmark and publish the available methodologies of model input uncertainty quantification relevant to the objectives of the benchmark. In this initial version the document was approved by WGAMA and has shown its usefulness during the subsequent phases of the project. Once Phase IV was completed, and following the suggestion of WGAMA members, the document was updated adding a few new sections, particularly the description of four new methodologies that were developed during this activity. Such developments were performed by some participants while contributing to PREMIUM progress (which is why this report arrives after those of other phases). After this revision the document title was changed to “PREMIUM methodologies and data review”. The introduction includes first a chapter devoted to contextualization of the benchmark in nuclear safety research and licensing, followed by a description of the PREMIUM objectives. Next, a description of the Phases in which the benchmark is divided and its organization is explained. Chapter two consists of a review of the involvement of the different participants, making a brief explanation of the input uncertainty quantification methodologies used in the activity. The document ends with some conclusions on the development of Phase I, some more general remarks and some statements on the benefits of the benchmark, which can be briefly summarized as it follows: - Contribution to development of tools and experience related to uncertainty calculation and promotion of the use of BEPU approaches for licensing and safety assessment purposes; - Contribution to prioritization of improvements to thermal-hydraulic system codes; - Contribution to a fluent and close interaction between the scientific community and regulatory organizations. Appendices include the complete description of the experimental data FEBA/SEFLEX used in the benchmark and the methodologies CIRCÉ and FFTBM and the general requirements and description specification used for Phase I. Due to the revision of the document, four extra appendixes have been added related to the methods developed during the activity, MCDA DIPE, Tractebel IUQ and PSI methods

What is the future for nuclear fission technology? A technical opinion from the Guest Editors of VSI NFT series and the Editor of the Journal Nuclear Engineering and Design

The Nuclear Fission Technology (NFT) series of Virtual Special Issues (VSIs) for the Journal Nuclear Engineering and Design (J NED) was proposed in 2023, including the request to potential authors of manuscript to address the following questions: o For how long will (water-cooling based) large size nuclear reactor survive? o Will water-technology based SMRs displace large reactors? o Will non-water-cooling technology SMRs and micro-reactors have an industrial deployment? o Will breeding technology, including thorium exploitation, have due relevance? o Will ‘nuclear infrastructure’ (fuel supply, financial framework, competence by regulators for new designs, waste management, etc.) remain or be sufficiently robust? Several dozen Guest Editors (GEs), i.e., the authors of the present document, managed the activity together with the Editor-in-Chief (EiC) of the journal. More than one thousand scientists contributed 470+ manuscripts, not evenly distributed among the geographical regions of the world and not necessarily addressing directly the bullet-questions, but certainly providing a view of current research being done. Key conclusions are as follows: (a) Large size reactors are necessary for a sustainable and safe exploitation of nuclear fission technology; (b) The burning of 233U (from thorium) and 239Pu (from uranium) is unavoidable, as well as recycling residual uranium currently part of waste; (c) Nuclear infrastructures in countries that currently use, or are entering the use of, fission energy for electricity production need a century planning; (d) The adoption of small reactors for commercial naval propulsion, hydrogen production and desalination is highly recommended

Assessment of a pressurizer spray valve faulty opening transient at Asco Nuclear Power Plant with RELAP5/MOD2. International Agreement Report

The Asociacion Nuclear Asco has prepared a model of Asco NPP using RELAP5/MOD2. This model, which include thermalhydraulics, kinetics and protection and controls, has been qualified in previous calculations of several actual plant transients. One of the transients of the qualification process is a ``Pressurizer spray valve faulty opening`` presented in this report. It consists in a primary coolant depressurization that causes the reactor trip by overtemperature and later on the actuation of the safety injection. The results are in close agreement with plant data

Preliminary Assessment of the Possible BWR Core/Vessel Damage States for Fukushima Daiichi Station Blackout Scenarios Using RELAP/SCDAPSIM

Immediately after the accident at Fukushima Daiichi, Innovative Systems Software and other members of the international SCDAP Development and Training Program started an assessment of the possible core/vessel damage states of the Fukushima Daiichi Units 1–3. The assessment included a brief review of relevant severe accident experiments and a series of detailed calculations using RELAP/SCDAPSIM. The calculations used a detailed RELAP/SCDAPSIM model of the Laguna Verde BWR vessel and related reactor cooling systems. The Laguna Verde models were provided by the Comision Nacional de Seguridad Nuclear y Salvaguardias, the Mexican nuclear regulatory authority. The initial assessment was originally presented to the International Atomic Energy Agency on March 21 to support their emergency response team and later to our Japanese members to support their Fukushima Daiichi specific analysis and model development