OCT4 controls mitotic stability and inactivates the RB tumor suppressor pathway to enhance ovarian cancer aggressiveness

OCT4 (Octamer-binding transcription factor 4) is essential for embryonic stem cell self-renewal. Here we show that OCT4 increases the aggressiveness of high-grade serous ovarian cancer (HG-SOC) by inactivating the Retinoblastoma tumor suppressor pathway and enhancing mitotic stability in cancer cells. OCT4 drives the expression of Nuclear Inhibitor of Protein Phosphatase type 1 (NIPP1) and Cyclin F (CCNF) that together inhibit Protein Phosphatase 1 (PP1). This results in pRB hyper-phosphorylation, accelerated cell proliferation and increased in vitro tumorigenicity of ovarian cancer cells. In parallel, OCT4 and NIPP1/CCNF drive the expression of the central Chromosomal Passenger Complex (CPC) components, Borealin, Survivin and the mitotic kinase Aurora B, promoting the clustering of supernumerary centrosomes to increase mitotic stability. Loss of OCT4 or NIPP1/CCNF results in severe mitotic defects, multipolar spindles and supernumerary centrosomes, finally leading to the induction of apoptosis. These phenotypes were recapitulated in different cancer models indicating general relevance for human cancer. Importantly, activation of these parallel pathways leads to dramatically reduced overall survival of HG-SOC patients. Altogether, our data highlights an unprecedented role for OCT4 as central regulator of mitotic fidelity and RB tumor suppressor pathway activity. Disrupting this pathway represents a promising strategy to target an aggressive subpopulation of HG-SOC cells.Oncogene advance online publication, 20 March 2017; doi:10.1038/onc.2017.20

A Protocol for Space Charge Measurements in Full-size HVDC Extruded Cables

This position paper, prepared by the IEEE DEIS HVDC Cable Systems Technical Committee, illustrates a protocol recommended for the measurement of space charges in full-size HVDC extruded cables during load cycle qualification tests (either prequalification load cycles or type test load cycles). The protocol accounts for the experimental practices of space charge measurements in the thick insulation of coaxial cables in terms of poling time, depolarization time, heating and cooling of specimens, as well as for the experience gained very recently from such kind of measurements performed in the framework of qualification tests relevant to ongoing HVDC cable system projects. The goal of the protocol is not checking the compliance with any maximum acceptable limit of either space charge or electric field. Rather, this protocol aims at assessing the variation of the electric field profile in the cable insulation wall during poling time at the beginning and at the end of load cycle qualification tests for full-size HVDC extruded cables. Indeed, in the design stage the electric field distributions are determined by the cable geometry and by temperature gradient in the insulation. Thus, the design is based on macroscopic parameters conductivity and permittivity and how they depend upon temperature. Any disturbance of the electric field due to space charge accumulation will only be revealed during space charge measurements either in as-manufactured state or in the aged state after load cycle qualification tests

DC Inclined-Plane Tracking and Erosion Test of Insulating Materials

The paper reviews previous work on the DC inclined plane test and suggests equivalent DC voltage levels in parallel to AC voltage in the ASTM inclined plane tracking and erosion test. The aim of this work is to provide a basis for standardizing the inclined plane test for DC voltage. Round robin tests done in five laboratories on five specimens of a silicone rubber material were done with the purpose of establishing appropriate ratios by which the equivalent DC voltages can be determined with respect to the corresponding AC voltages. These levels were determined as 67% and 87%, for +DC and-DC respectively, of the AC initial tracking voltage, and for practical purposes, these levels are rounded to 70 and 90%.Peer reviewed: YesNRC publication: Ye

Mismatch repair system in endometriotic tissue and eutopic endometrium of unaffected women

9Objective: To test the immunohistochemical staining pattern of some mismatch repair (MMR) system proteins in endometriotic tissue (ET) and eutopic endometrium. Methods: This was a retrospective study conducted at the Pathology and Obstetrics and Gynecology Departments of the Udine University Hospital. We analyzed 528 samples obtained from 246 patients affected by endometriosis and 71 samples from 71 patients with normal endometrium. A tissue microarray model was used to analyze the immunohistochemical expression of MMR system proteins. Results: Significant loss of MMR proteins was found in the stromal component of ETs. We found MSH2 to be expressed at a higher level than any other MMR system proteins in eutopic endometrium and ETs, to be significantly correlated to Ki-67 expression in both stromal and glandular components of ETs, and to be expressed at a significantly higher level in ETs than in eutopic endometrium. When considering the subgroup of endometriosis with high recurrence rate and glandular cytoplasmic staining for aurora A kinase, we found MMR proteins expressed at a significantly higher level in these ETs than in other ETs and eutopic endometrium of unaffected women. Conclusions: We found significant loss of MMR proteins (known to be associated with microsatellite instability) in the stromal component of ETs. The group of ETs with glandular cytoplasmic staining for aurora A kinase had higher MMR protein expression, suggesting an increased activity of this system. Our result suggests a novel role of increased MSH2 expression in cellular proliferation of endometriosis.openopenGrassi, T.; Calcagno, A.; Marzinotto, S.; Londero, A.P.; Orsaria, M.; Canciani, G.N.; Beltrami, C.A.; Marchesoni, D.; Mariuzzi, L.Grassi, T.; Calcagno, A.; Marzinotto, S.; Londero, Ambrogio P.; Orsaria, M.; Canciani, G. N.; Beltrami, Carlo Alberto; Marchesoni, Diego; Mariuzzi, Laur

Application of an artificial intelligence algorithm to prognostically stratify grade II gliomas

(1) Background: Recently, it has been shown that the extent of resection (EOR) and molecular classification of low-grade gliomas (LGGs) are endowed with prognostic significance. However, a prognostic stratification of patients able to give specific weight to the single parameters able to predict prognosis is still missing. Here, we adopt classic statistics and an artificial intelligence algorithm to define a multiparametric prognostic stratification of grade II glioma patients. (2) Methods: 241 adults who underwent surgery for a supratentorial LGG were included. Clinical, neuroradiological, surgical, histopathological and molecular data were assessed for their ability to predict overall survival (OS), progression-free survival (PFS), and malignant progression-free survival (MPFS). Finally, a decision-tree algorithm was employed to stratify patients. (3) Results: Classic statistics confirmed EOR, pre-operative-and post-operative tumor volumes, Ki67, and the molecular classification as independent predictors of OS, PFS, and MPFS. The decision tree approach provided an algorithm capable of identifying prognostic factors and defining both the cut-off levels and the hierarchy to be used in order to delineate specific prognostic classes with high positive predictive value. Key results were the superior role of EOR on that of molecular class, the importance of second surgery, and the role of different prognostic factors within the three molecular classes. (4) Conclusions: This study proposes a stratification of LGG patients based on the different combinations of clinical, molecular, and imaging data, adopting a supervised non-parametric learning method. If validated in independent case studies, the clinical utility of this innovative stratification approach might be proved

The Insulation of HVDC Extruded Cable System Joints. Part 2: Proposal of a New AC Voltage PD Measurement Protocol for Quality Control during Routine Tests

The review of materials, design and testing of joints for HVDC extruded cable systems provided in previous Part 1 paved the way to this Part 2 position paper by the DEIS HVDC Cable Systems Technical Committee, whose aim is to remedy the scarcity of existing standardized tests on joints. After a sound analysis, here routine tests are identified as the first practical target for the onset of new testing procedures, AC-PD measurements as the readily-available measurement from manufacturers’ experience for quality control of joints during routine tests and VHF/UHF wireless sensors as the best tool for such measurements in the noisy environment of factories. Thereby, a novel protocol for PD measurement using AC voltages and VHF/UHF electromagnetic sensors, for quality control during routine tests on HVDC extruded joints, is proposed

The Insulation of HVDC Extruded Cable System Joints. Part 1: Review of Materials, Design and Testing Procedures

This position paper by the DEIS HVDC Cable Systems Technical Committee provides a review of existing diagnostic electrical and dielectric techniques for testing the insulation of polymeric extruded HVDC cable joints in the present Part 1. Here, the state of the art on the insulation of HVDC extruded cable system joints is covered with reference to types, design and testing techniques. This helps to identify routine tests as the first target for the onset of new testing procedures, AC-PD measurements as the readily-available measurement from manufacturers' practices for quality control of the insulation of accessories during routine tests and VHF/UHF wireless sensors as the best tool for performing such measurements on joints in the noisy factory environment. Thereby, a novel protocol for the measurement of partial discharges using AC voltages and VHF/UHF sensors, for quality control during routine tests on such joints, is derived in the next Part 2. This protocol is the main novelty of this investigation

Autoantibodies toward ATP4A and ATP4B subunits of gastric proton pump H+,K+-ATPase are reliable serological pre-endoscopic markers of corpus atrophic gastritis

INTRODUCTION: Noninvasive assessment of corpus atrophic gastritis (CAG), a condition at increased risk of gastric cancer, is based on the measurement of pepsinogens, gastrin, and Helicobacter pylori antibodies. Parietal cell autoantibodies (PCAs) against the gastric proton pump (ATP4) are potential serological biomarkers of CAG. The purpose of this study was to compare the diagnostic performance of PCA and pepsinogen I tests in patients with clinical suspicion of CAG with the histopathological evaluation of gastric biopsies as reference standard. METHODS: A prospective case-finding study was performed on 218 naive adult patients (131 women, median age 65 years) who underwent gastric biopsies to confirm/exclude CAG. Patients with histopathological CAG were defined as cases, conversely as controls. Autoantibodies against the individual alpha (ATP4A) and beta (ATP4B) subunits of ATP4 were measured by luciferase immunoprecipitation, and global PCA and pepsinogen I by enzyme-linked immunosorbent assay. RESULTS: Histopathology classified 107 subjects (49%) as cases (CAG+, autoimmune 81.2%, and multifocal extensive 18.8%) and 111 subjects (51%) as controls (CAG−). In cases, ATP4A, ATP4B, and PCA titers were increased compared with controls, whereas pepsinogen I was reduced (P < 0.0001 for all). ATP4B, ATP4A, and pepsinogen I tests showed sensitivities of 77%, 75%, and 73% and specificities of 88%, 88%, and 80%, respectively. The receiver operating characteristic (ROC) area under the ROC curve (AUC) of these serological biomarkers confirmed their ability to discriminate cases from controls (ATP4B = 0.838, ATP4A = 0.826, pepsinogen I = 0.775, and PCA = 0.805), whereas the partial ROC-pAUC90 analysis showed that the ATP4B test had the best diagnostic performance (P = 0.008 vs ATP4; P = 0.0002 vs pepsinogen I). The presence of autoimmune or extensive gastritis was not significantly different between ATP4B positive or negative cases (P = 0.217). DISCUSSION: PCAs are promising serological biomarkers for the identification of CAG in high-risk individuals, particularly in an autoimmune pattern but also in an extensive-multifocal atrophy pattern