The PI3K/AKT pathway is considered to play a major role in bladder carcinogenesis, but its relationships with other molecular alterations observed in bladder cancer remain unknown. We investigated ...PI3K/AKT pathway activation in a series of human bladder urothelial carcinomas (UC) according to PTEN expression, PTEN deletions and FGFR3, PIK3CA, KRAS, HRAS, NRAS and TP53 gene mutations. The series included 6 normal bladder urothelial samples and 129 UC (Ta n = 25, T1 n = 34, T2–T3–T4 n = 70). Expression of phospho‐AKT (pAKT), phospho‐S6‐Ribosomal Protein (pS6) (one downstream effector of PI3K/AKT pathway) and PTEN was evaluated by reverse phase protein Array. Expression of miR‐21, miR‐19a and miR‐222, known to regulate PTEN expression, was also evaluated. pAKT expression levels were higher in tumors than in normal urothelium (p < 0.01), regardless of stage and showed a weak and positive correlation with pS6 (Spearman coefficient RS = 0.26; p = 0.002). No association was observed between pAKT or pS6 expression and the gene mutations studied. PTEN expression was decreased in PTEN‐deleted tumors, and in T1 (p = 0.0089) and T2–T3–T4 (p < 0.001) tumors compared to Ta tumors; it was also negatively correlated with miR‐19a (RS = −0.50; p = 0.0088) and miR‐222 (RS = −0.48; p = 0.0132), but not miR‐21 (RS = −0.27; p = 0.18) expression. pAKT and PTEN expressions were not negatively correlated, and, on the opposite, a positive and moderate correlation was observed in Ta (RS = 0.54; p = 0.0056) and T1 (RS = 0.56; p = 0.0006) tumors. Our study suggests that PI3K/AKT pathway activation occurs in the entire spectrum of bladder UC regardless of stage or known most frequent molecular alterations, and independently of low PTEN expression.
What's new?
Although a suspected player in bladder carcinogenesis, involvement of the PI3K/AKT pathway in human bladder urothelial carcinoma (UC) has been little explored. Here, reverse phase protein array was used to investigate PI3K/AKT pathway activation and expression of PTEN, a PI3K/AKT pathway downregulator, in a series of human UCs characterized by genetic alterations frequently observed in UC. Analysis revealed elevated pAKT expression and PI3K/AKT pathway activation across UCs, despite the different molecular alterations and independent of the loss of PTEN. The findings support the idea that the PI3K/AKT pathway is of therapeutic significance in UC.
Purpose
This paper aims at an analytical approach-based prediction of the eddy current
loss in the PMs of a concentrated winding machine equipped with 12 slots in the stator and 10
poles in the ...rotor.
Design/methodology/approach
The investigation of the PM eddy current loss has been carried out using an analytical model and a 2D time-stepped transient finite element analysis
(FEA).
Findings
It has been found, in the case of the treated machine, that just the subharmonic
of rank one and the harmonic of rank seven have significant contributions to the eddy current
loss in the PMs.
Research limitations/implications
A shift between the results yielded by the developed
analytical model and those computed by FEA has been noticed. This limitation is mainly due
to the slotting effect which has been omitted in the analytical model.
Practical implications
Fractional slot PM machines are currently given an increasing attention in automotive applications. The prediction of their iron loss in an attempt to rethink
their design represents a crucial efficiency benefit.
Originality/value
The analytical prediction of the eddy current loss in each PM then in all PMs and their validation by FEA represent the major contribution of this work.
We present a new integrated electromechanical set for automotive hybrid propulsion systems. It consists of two concentric permanent-magnet (PM) machines with inner and outer surface-mounted PM ...rotors, and a stator sandwiched between the two rotors, yielding a so-called ldquosingle-stator dual-rotor PM machinerdquo. The stator magnetic circuit consists of two concentric parts decoupled by a nonmagnetic ring. In an earlier topology, distributed windings were used in both stators. We substitute concentrated windings to extend the flux weakening range. We discuss our investigation of the magnetomotive force (MMF) spatial profile and of the torque production capability of this dedicated concentrated winding surface-mounted PM machine.
The paper deals with a 3-D analytical model by considering the end effect which is dedicated to the prediction of the permanent-magnet (PM) eddy-current loss in fractional-slot permanent-magnet ...machines. Following the derivation of the proposed model, it is applied to the case of a 12-slot 10-pole machine with unsegmented PMs operating at rated speed. A good agreement is found while comparing the analytical results and those computed by 3-D finite element analysis. In the next step, the proposed model is applied to the investigation of the effect of PM segmentation on the reduction of their eddy-current loss, considering: 1) the radial segmentation and 2) the axial one. The obtained results highlight the better capability exhibited by the radial segmentation over the axial one in reducing the PM eddy-current loss. Finally, the proposed analytical model is applied to the investigation of the coupled-effects of the PM segmentation and geometry on their eddy-current loss reduction.
Epigenetic modification is one of the mechanisms leading to gene silencing in neoplastic cells. By methylation-specific PCR, we analyzed the promoter methylation of three cancer-related genes: Ras ...Association domain Family 1A (RASSF1A), Death Associated Protein kinase (DAP-kinase) and Retinoic Acid Receptor β2 (RARβ2) in two NPC xenografts (C15 and C17), 68 primary NPC tumors, and nine normal nasopharyngeal epithelia. We showed that C15 and C17 displayed a complete promoter methylation of RASSF1A, RARβ2 and DAP-kinase genes. In primary NPC tumors, the incidence of promoter methylation was very high for all three tested genes: 91% for RASSF1A, 88% for both RARβ2 and DAP-kinase whereas all normal nasopharyngeal epithelia were unmethylated. Interestingly, our study revealed that aberrant promoter methylation of the three genes were statistically associated with the lymph node involvement (p < 0.0001). In addition, hypermethylation of RASSF1A was correlated with age at diagnosis (p = 0.047) and T stage (p = 0.037) while the RARβ2 hypermethylation was associated with histological type (p = 0.011). Taken together, our results demonstrate that silencing of RASSF1A and RARβ2 expression by promoter hypermethylation is associated with highly differentiated tumors, advanced tumor stage and the presence of lymph node metastasis.
To assess the functional significance of the epigenetic silencing of RARβ2 and DAP-kinase in NPC, we analysed the expression of two downstream target genes COX-2 and p53 by reverse PCR (RT-PCR) and immunohistochemistry (IHC). We revealed a significant association between expression of COX-2 and loss of RARβ2 through aberrant methylation (p = 0.003) in NPC biopsies.
We concluded that the inactivation of RASSF1A, RARβ2 and DAP-Kinase by hypermethylation is a key step in NPC tumorigenesis and progression.
Purpose
– The purpose of this paper is to compare the study between two topologies of fractional-slot permanent-magnet machines such that: double-layer topology and single-layer one. The comparison ...considers the assessment of the iron loss in the laminated cores of the magnetic circuit as well as in the permanent magnets (PMs) for constant torque and flux weakening ranges.
Design/methodology/approach
– The investigation of the hysteresis and eddy-current loss has been carried out using 2D transient FEA models.
Findings
– It has been found that the stator iron losses are almost the same for both topologies. Whereas, the single-layer topology is penalized by higher iron loss especially the eddy-current ones taking place in the PMs. This is due to their denser harmonic content of the armature air gap MMF spatial repartition.
Originality/value
– The analysis of the iron loss maps in different parts of each machine including stator and rotor laminations as well as the PMs, in one hand, and the investigation of their variation with respect to the speed, in the other hand, represent the major contribution of this work.
The objective of this study is to experimentally determine the sorption isotherms and thermodynamic properties of green mint after undergoing thermal and biochemical treatment. The method employed is ...the gravimetric method using saturated saline solutions at various temperatures. In order to model and predict the hygroscopic behavior during drying and storage, we have utilized developed mathematical models (such as the Langmuir, GAB, modified BET, Peleg models, etc.). The adjustment and optimization of these models will be conducted using statistical techniques to analyze the obtained data. The isosteric desorption heats of green mint will be calculated using the Clausius-Clapeyron equation. This study will provide an expression to predict the thermodynamic properties of green mint.
Les tumeurs de vessie suivent deux voies de progression tumorale. La voie des tumeurs papillaires qui progressent rarement vers des tumeurs invasives mais qui récidivent très fréquemment et la voie ...des carcinomes in situ (CIS) qui progressent pour envahir le chorion puis le muscle. Les tumeurs infiltrant le muscle sont de mauvais pronostic et les traitements par chimiothérapie restent d’efficacité limitée. Il est alors important d’en comprendre les bases moléculaires. Les microRNAs sont d’importants régulateurs de l’expression post-transcriptionnelle des gènes. Des perturbations de leur expression et/ou de leur activité contribuent au développement tumoral en dérégulant l’expression de gènes clés dans les cancers. Nos travaux ont porté sur l’étude de l’expression et des fonctions des microRNAs dans la carcinogenèse urothéliale. Dans la première partie, nous avons choisi d’étudier, par une approche de gènes candidats, miR-155, un oncomiR dont l’expression dérégulée a été rapportée dans plusieurs cancers mais pas encore dans le cancer de la vessie. J’ai identifié une surexpression significative de ce miARN dans un sous-groupe de cancers invasifs de vessie. Ensuite, j’ai montré par des analyses fonctionnelles, le rôle de miR-155 dans l’invasion et la migration tumorale mais pas dans la prolifération cellulaire. Dans la deuxième partie, nous avons utilisé une approche plus globale. J’ai d'abord effectué une revue extensive de la littérature pour rechercher les miR dont l'expression avait été montrée comme dérégulée dans les cancers de vessie et/ou les miR impliqués fonctionnellement dans ce cancer. J’ai ensuite réalisé une analyse multiparamétrique en intégrant les données d'expression de ces miR, les données anatomopathologiques et moléculaires (stade et grade, statut mutationel de TP53 et FGFR3, phénotype épigénétique MRES et signature CIS) et les données du transcriptome (puces Affymetrix U133 Plus 2.0), des altérations génomiques (puces Illumina 370.000 sondes) et de méthylation (puces Illumina 27.000 sondes). Ce travail m’a permis, d'identifier des miR associés à l'une des deux voies de progression identifiées dans les cancers de vessie et de proposer des cibles candidates de ces miR. La recherche des altérations épigénétiques pouvant affecter l’expression de ces miR a permis d’identifier une association significative entre l’expression d’un miARN (miR-17-5p) et la méthylation d’un promoteur. En revanche les altérations génétiques n’ont été associées à aucune expression de miR. Ce travail propose une liste de très bons candidats miARNs pour lesquels des études fonctionnelles pourront être envisagées au-delà de mon travail de thèse.
Bladder tumors are characterized by two progression pathways. The first pathway leads to the developpement of papillary tumors, which are at high risk of recurrence but that rarely progress to invasive tumors. Another pathway involves carcinoma in situ (CIS), which often progresses by first invading the lamina propria and then the muscle. Tumors infiltrating the muscle have a poor prognosis and chemotherapy regimens are of limited benefits. It is yet important to understand the molecular basis underlying these events. The microRNAs are important regulators of post-transcriptional gene expression. Alteration in their expression and /or activity is believed to contribute to tumor development by deregulating the expression of cancer-related genes. Our work has been focused on studying the expression and function of microRNAs in urothelial carcinogenesis. In the first part, we employed a candidate gene approach to study miR-155, a oncomiR whose dysregulated expression has been reported in many cancers, but not in bladder cancer. I identified a significant overexpression of this miRNA in a subgroup of invasive bladder cancers. Next, I demonstrated a role for miR-155 in tumor invasion and migration, without any apparent effect on cell proliferation. In the second part, we used a more comprehensive approach in which I first conducted an extensive review of the literature to search for miR whose expression was already found to be deregulated and/or miR functionally involved in bladder cancer. I then performed a multiparametric analysis by integrating expression data of miR, pathological and molecular data (stage and grade, mutational status of FGFR3 and TP53, MRES epigenetic phenotype and CIS signature) data of the transcriptome (Affymetrix U133 Plus 2.0), genomic alterations (370,000 chips Illumina probes) and methylation (Illumina chips 27,000 probes). This work allowed us to identify miRs associated with one or the other pathway linked to progression of bladder cancer and also, it revealed candidate targets for these miRs. The search for epigenetic alterations capable to affect the expression of those miRs showed significant association between expression of a particular miRNA (miR-17-5p) and the methylation of its promoter. Genetic alterations however, have failed to associate with expression of miR. Finally, this work suggests a list of good candidates miRNAs for which future functional studies should help to get insight into the role of these miRNAs
The estimation of PM eddy current loss in fractional slot PM machines (FSPMMs) is of great importance since it is closely related to the prediction of their efficiency. This issue turns to be ...critical accounting for the FSPMMs capability to achieve a wide speed range. The paper is devoted to a 3D FEA-based investigation of the effect of PM segmentation on the variation of their eddy current losses at load operation constant power and flux weakening range operating points in a 12 slot/10 pole FSPMM. The developed study considers three different segmentation configurations, such that: (i) the radial segmentation, (ii) the axial segmentation, and (iii) the axial-skewed segmentation. The postprocessing of FEA models yields the time variation of eddy current loss in each PM segment as well as the loss density maps in the PMs for each segmentation configuration. It has been found that the radial segmentation is more effective than the other configurations.
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