Expression de marqueurs pro-oncogéniques dans les phases précoces de la carcinogénèse colorectale

Les polypes hyperplasiques (PH) constituent les lésions colorectales les plus fréquentes. Ces lésions ont pendant longtemps été considérées comme des lésions sans potentiel malin et le suivi coloscopique des patients ayant développé des PH n'est pas recommandé. Récemment, plusieurs études suggèrent qu'une partie de ces polypes pourrait constituer des précurseurs de certains cancers colorectaux sporadiques. Cependant, aucun biomarqueur permettant de détecter les PH à risque d'évolution maligne n'a pu être identifié. La progastrine est une prohormone impliquée dans la carcinogénèse colique. Dans un premier temps, nous avons étudié l'expression de la progastrine dans des PH provenant de 74 patients sans antécédent de pathologie colorectale et avons mis en évidence une surexpression de la prohormone dans 40% des cas. Dans un sous-échantillon composé de 39 patients pour lesquels un suivi coloscopique avait été réalisé, 41% des patients ayant présenté un PH ont développé des polypes adénomateux métachrones. Nous avons pu montrer une association significative entre l'expression de la progastrine et la survie sans néoplasme (p=0.001). En effet, la survie sans néoplasme à 5 ans était de 38% chez les patients présentant une forte surexpression de progastrine alors qu'elle était de 100% chez les patients avec une faible expression. Par ailleurs, nous avons démontré qu'un test prédictif composite basé sur le marquage de la progastrine et l'âge des patients permettraient de prédire la survenue d'un événement néoplasique métachrone chez les patients ayant développé un PH avec une sensibilité de 100% (Intervalle de confiance à 95% : 79%-100%) et une spécificité de 74% (51%-90%). La progastrine peut activer plusieurs voies pro-oncogéniques dans les cancers colorectaux. Certaines d'entre elles, en particulier les voies JAK/STAT ou ERK n'ont pas encore été explorées dans les polypes hyperplasiques. Afin de mieux caractériser les polypes exprimant la progastrine, nous avons, dans un second temps, étudié l'activation de STAT3 et ERK dans un deuxième échantillon de 49 polypes hyperplasiques. Le pourcentage de cellules marquées par des anticorps spécifiques anti-progastrine, anti-phospho-STAT3 et anti-phospho-ERK étaient en moyenne de 31% (écart-type : 35), 10% (23) et 34% (30%), respectivement et étaient significativement augmentée dans les PH par rapport aux tissus normaux contrôles pour la progastrine et P-ERK (p=0,0008 et 0.0003). De plus, l'augmentation progressive de l'expression de ces deux marqueurs entre le tissu normal, les PH, les adénomes de dysplasie légère, modérée et sévère étaient significative (p<0.0001 pour la progastrine et p=0.001 pour P-ERK) et suggèrent une activation de ces deux facteurs dans les PH intermédiaire entre le colon normal et les adénomes. Nous avons également montré, dans ces lésions, que l'expression de la progastrine était corrélée à celle de P-ERK (p=0,0184). L'ensemble de ces résultats suggèrent que la progastrine pourrait être associée à un sous-type de PH à risque d'évolution maligne et permettre de l'identifier.The most frequently occurring lesions in the colon are the hyperplastic polyps (HP). HP have long been considered as lesions with no malignant potential and colonoscopy for these patients is not recommended. However recent works suggest that HP may represent precursor lesions of some sporadic colorectal cancers. Until now, none biomarker allows to identify the subset of HP that may have a malignant potential. Because the hormone precursor, progastrin has been involved in colon carcinogenesis, we, firstly, investigated whether its expression in HP predicts occurrence of colonic neoplasm after resection of HP. We retrospectively analyzed progastrin expression in HP from 74 patients without history of colorectal pathology. In our study, 41% of patients presenting an initial HP subsequently developed adenomatous polyps, recognized as precursor lesions for colorectal adenocarcinomas. Progastrin was overexpressed in the HP in 40% of the patients. We showed a significant association between progastrin overexpression and shortened neoplasm-free survival (P= 0.001). Patients with high overexpression of progastrin had a 5 year neoplasm-free survival of 38% as compared to 100% for the patients with low progastrin expression. In addition, we established a predictive test based on progastrin staining and patient's age that predicts occurrence of neoplasm after developing a first HP with a sensitivity of 100% (95%CI: 79%-100%) and a specificity of 74% (51%-90%). We show that progastrin expression evaluation in HP is an efficient prognostic tool to determine patients with higher risk of metachronous neoplasms who could benefit from an adapted follow-up. Progastrin has been shown to activate several pro-oncogenic pathways. Since ERK and STAT3 activation have not been explored yet in HP and to better characterize progastrin positive HP, we, secondly, assessed the activation of these two pro-oncogenic factors in HP and their association to progastrin expression in a second sample of 49 HP. The average percentages of progastrin-, phospho-STAT3- and phospho-ERK1/2- epithelial stained cells in HP were, respectively, 31% (standard deviation: 35), 10% (23) and 34% (30%). The expression levels of progastrin and phospho-ERK were higher in these lesions compared to normal colon (p=0,0008 et 0.0003, respectively). Moreover, the progressive increase of progastrin and phospho-ERK staining in normal colon, HP and adenoma was significant (p<0.0001 and p=0.001, respectively) and suggests that expression of these factors in HP is intermediate between normal mucosa and colonic adenomas. We also found a significant correlation between progastrin and phospho-ERK expression in HP (p=0,0184). Taken together, our results suggest that progastrin expression might be associated to HP with malignant potential and can help to identify this subset of HP

Impact of wind and solar production on electricity prices: Quantile regression approach

This is is an Accepted Manuscript of an article published by Taylor & Francis in Journal of the Operational Research Society on 5 August 2019, available online: http://www.tandfonline.com/10.1080/01605682.2019.1634783.We study the impact of fuel prices, emission allowances, demand, past prices, wind and solar production on hourly day-ahead electricity prices in Germany over the period from January 2015 until June 2018. Working within a linear regression, ARX-EGARCH and quantile regression framework we compare how different pricing factors influence the mean and quantiles of the electricity prices. Contrary to the existing literature, we find that short-term price fluctuations on the fuel markets and emission allowances have little effect on the electricity prices. We also find that day-of-the-week as well as monthly effects have significant impact on the electricity prices in Germany and should not be ignored in model specifications. Three main factors are found to drive extreme prices: price persistence, expected demand and expected wind production. Our findings contribute to understanding of extreme price movements, which can be used in pricing models and hedging strategies.acceptedVersio

Dications of Benzylidenefluorene and Diphenylmethylidene Fluorene: The Relationship between Magnetic and Energetic Measures of Antiaromaticity

Oxidation of m- and p-substituted benzylidene fluorenes to antiaromatic dications was attempted by electrochemical and chemical means. Electrochemical oxidation to dications was successful for benzylidene fluorenes with p-methoxy, p-methyl, p-fluoro, and unsubstituted phenyl rings in the 3-position; attempts to oxidize the m-substituted derivatives via electrochemistry were unsuccessful. Chemical oxidation with SbF5/SO2ClF gave the dication of 9-[(4-methoxyphenyl)methylene]-9H-fluorene cleanly; oxidation of all other substituted benzylidene fluorenes resulted in mixtures of products. The excellent linear relationship between the chemical shifts calculated by the GIAO method and the experimental shifts for the p-methoxy-substituted benzylidene fluorene dication suggests that the calculations satisfactorily reflect the magnetic properties of this dication and potentially those of the other dications studied. The redox potentials from electrochemical oxidation, a measure of the stability of the dications, showed a good linear relationship with another measure of stability, the calculated difference in energy between each dication and its neutral precursor. The dications of benzylidene fluorenes were less stable than the dications of diphenylmethylidene fluorenes; within each type of compound, dications withp-substituted phenyl rings were more stable than dications with m-substituted phenyl rings and dications with phenyl rings substituted with electron-donating groups were more stable than dications with phenyl rings substituted with electron-withdrawing groups. The antiaromaticity of the fluorenyl system was assessed through the nucleus-independent chemical shift (NICS) that was also calculated by the GIAO method. The plot of the NICS values per square area versus the calculated energy difference for the dications showed a moderate degree of linearity; the plot of NICS values per square area versus the oxidation potentials was less linear. Thus, a suggestive, but not conclusive, relationship between magnetic and energetic measures of antiaromaticity was observed

Finerenone: A New Era for Mineralocorticoid Receptor Antagonism and Cardiorenal Protection.

The renin-angiotensin-aldosterone system is a neurohormonal system responsible for maintaining homeostasis of fluid regulation, sodium balance, and blood pressure. The complexity of this pathway enables it to be a common target for blood pressure and volume-regulating medications. The mineralocorticoid receptor is one of these targets, and is found not only in the kidney, but also tissues making up the heart, blood vessels, and adipose. Mineralocorticoid receptor antagonists have been shown to slow progression of chronic kidney disease, treat refractory hypertension and primary aldosteronism, and improve morbidity and mortality in management of heart failure with reduced ejection fraction. The more well-studied medications were derived from steroid-based compounds, and thus come with a distinct side-effect profile. To avoid these adverse effects, developing a mineralocorticoid receptor antagonist (MRA) from a non-steroidal base compound has gained much interest. This review will focus on the novel non-steroidal MRA, Finerenone, to describe its unique mechanism of action while summarizing the available clinical trials supporting its use in patients with various etiologies of cardiorenal disease

Opinião dissidente do Juiz Cançado Trindade junto ao Acórdão da Corte Internacional de Justiça, de 3 de fevereiro de 2012, no caso das Imunidades Jurisdicionais do Estado (Alemanha c. Itália; Grécia (interveniente)) – tradução do original

Dissenting opinion of Judge Cançado Trindade in the case of Jurisdictional Immunities of the State brought by Germany before the IC

MYC is a critical target of FBXW7

MYC deregulation is a driver of many human cancers. Altering the balance of MYC protein levels at the level of transcription, protein stability, or turnover is sufficient to transform cells to a tumorigenic phenotype. While direct targeting of MYC is difficult, specific genetic vulnerabilities of MYC-deregulated cells could be exploited to selectively inhibit their growth. Using a genome-wide shRNA screen, we identified 78 candidate genes, which are required for survival of human mammary epithelial cells with elevated MYC levels. Among the candidates, we validated and characterized FBXW7, a component of the SCF-like ubiquitin ligase complex that targets MYC for proteasomal degradation. Down-regulation of FBXW7 leads to synergistic accumulation of cellular and active chromatin-bound MYC, while protein levels of other FBXW7 targets appear unaffected. Over a four-week time course, continuous FBXW7 down-regulation and MYC activation together cause an accumulation of cells in S-phase and G2/M-phase of the cell cycle. Under these conditions, we also observe elevated chromatin-bound levels of CDC45, suggesting increased DNA replication stress. Consistent with these results, FBXW7 down-regulation alone decreases the survival of T47D breast cancer cells. These results establish that FBXW7 downregulation is synthetic lethal with MYC, and that MYC is a critical target of FBXW7 in breast epithelial cells

MYC is a critical target of FBXW7

MYC deregulation is a driver of many human cancers. Altering the balance of MYC protein levels at the level of transcription, protein stability, or turnover is sufficient to transform cells to a tumorigenic phenotype. While direct targeting of MYC is difficult, specific genetic vulnerabilities of MYC-deregulated cells could be exploited to selectively inhibit their growth. Using a genome-wide shRNA screen, we identified 78 candidate genes, which are required for survival of human mammary epithelial cells with elevated MYC levels. Among the candidates, we validated and characterized FBXW7, a component of the SCF-like ubiquitin ligase complex that targets MYC for proteasomal degradation. Down-regulation of FBXW7 leads to synergistic accumulation of cellular and active chromatin-bound MYC, while protein levels of other FBXW7 targets appear unaffected. Over a four-week time course, continuous FBXW7 down-regulation and MYC activation together cause an accumulation of cells in S-phase and G2/M-phase of the cell cycle. Under these conditions, we also observe elevated chromatin-bound levels of CDC45, suggesting increased DNA replication stress. Consistent with these results, FBXW7 down-regulation alone decreases the survival of T47D breast cancer cells. These results establish that FBXW7 down-regulation is synthetic lethal with MYC, and that MYC is a critical target of FBXW7 in breast epithelial cells