Global longitudinal strain (GLS) has several sources of variation. Strain multilayer tracking is a new tool that has not yet been validated in clinical practice.
The purpose of this study was to ...investigate intervendor variability when measuring multilayer strain in patients receiving chemotherapy for cancer.
Patients receiving chemotherapy for cancer, who were referred for echocardiography, were included prospectively. First, the same operator performed two-dimensional echocardiography on each patient using the Vivid E9™ (General Electric, Fairfield, CT, USA) and the ACUSON SC2000™ (Siemens, Munich, Germany) ultrasound systems. Second, we assessed myocardial deformation by using their respective speckle-tracking software. Third, we compared absolute values of GLS for the two vendors in each apical view (four-, three- and two-chamber) and for each layer (endocardial, mid-myocardial and epicardial).
Eighty patients with cancer were included prospectively between February and June 2015. For a given vendor, GLS values decreased from the endocardial layer to the epicardial layer. For a given view, GLS values obtained with the ACUSON SC2000 platform were systematically lower than those obtained with the Vivid E9 platform (P<0.0001). We observed a significant difference between the two platforms, irrespective of the layer, interlayer gradient or chamber view considered (P<0.0001).
There was poor agreement for layer-specific strain evaluation between the Vivid E9 and ACUSON SC2000 platforms, using their dedicated software for strain multilayer assessment. These results suggest that, in clinical practice, the same system and software from the same vendor should be used for longitudinal follow-up.
Le strain longitudinal global (SLG) a de multiples causes de variabilité. Le strain multicouche mesuré par la méthode de speckle tracking est un outil n’ayant pas encore été validé dans la pratique clinique.
L’objectif de cette étude était d’évaluer la variabilité intervendeur de la mesure du strain multicouche chez des patients suivis pour une néoplasie recevant des chimiothérapies.
Les patients recevant une chimiothérapie dans le cadre du traitement de cancer, adressés pour une échographie cardiaque ont été inclus de manière prospective. Premièrement, le même opérateur a réalisé une échographie 2D à chaque patient en utilisant 2 échographes, le Vivid E9™ (General Electric, Fairfield, CT, États-Unis) et l’ACUSON SC2000™(Siemens, Munich, Allemagne). Deuxièmement, nous avons évalué la déformation myocardique en utilisant leur logiciel respectif de speckle tracking dédié à la mesure du strain multicouche. Troisièmement, nous avons comparé les valeurs absolues de SLG des 2 constructeurs dans chaque incidence apicale (4-, 3- et 2- cavités) et pour chaque couche (endocarde, couche myocardique moyenne et épicarde).
Quatre-vingt patients traités pour un cancer ont été inclus prospectivement entre février et juin 2015. Pour chaque constructeur, les valeurs de SLG diminuaient de la couche endocardique vers la couche épicardique. Pour une incidence donnée, les valeurs de SLG avec la machine ACUSON SC2000 étaient systématiquement plus faibles que celles obtenues avec la machine Vivid E9 (p<0,001). Nous avons observé une différence significative des valeurs de strain multicouche entre les 2 constructeurs que l’on considère la couche myocardique, le gradient intercouche ou l’incidence apicale (p<0,0001).
Il y avait une faible concordance entre le Vivid E9 et l’ACUSON SC2000 en utilisant leur logiciel dédié pour l’évaluation du strain multicouche. Ces résultats suggèrent que pour la pratique clinique, la même machine et logiciel du même constructeur soient utilisés pour le suivi des patients.
Telomeres and telomerase have been subjects to a tremendous attention from scientists and oncologists during the past 5 years. This interest has been motivated by the potential of telomerase as a ...tumor marker for the diagnosis and the prognosis of cancer. The possible use of telomerase or telomeres as new targets for anticancer drugs also triggered investigations. The expression of telomerase was found in overall 85% of cancers. Telomerase is early expressed during oncogenesis with a gradient indicating that a high level of telomerase expression could be associated with a bad prognosis. Therefore, drugs targeting telomerase and telomeres might be useful in many human tumors with little restrictions regarding the tumor type or on the stage of the disease. Moreover, since telomerase is not or slightly expressed in normal cells, it has been postulated that drugs targeting telomerase would induce low toxicity. The race for the discovery of telomerase inhibitors has started while the identification of the components controlling telomerase, telomeres, cell survival, senescence, and apoptosis was still in progress. The recent identification of components regulating telomere length and telomerase expression (TRF1, TRF2, and tankyrase) opened a variety of new opportunities to control telomerase/telomere interactions. Meanwhile, a proof of principle was provided that changing telomere interactions with telomere binding proteins by chemical or biological means can induce cancer cell death. Interestingly, recent data challenge the old paradigm which suggested that a long exposure to telomerase and telomere inhibitors is necessary to induce anticancer effects. In this paper, we review the most recent information concerning the regulation of telomere length and telomerase expression, with emphasis on mechanisms that might translate into new drug discovery.
Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. Excision repair cross-complementation group 1 (ERCC1) deficiency is frequently found in ...non-small-cell lung cancer (NSCLC), making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in the disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house-generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). We also found reduced NAMPT expression in NSCLC samples with low levels of ERCC1. These metabolic alterations were a primary effect of ERCC1 deficiency, and caused selective exquisite sensitivity to small-molecule NAMPT inhibitors, both in vitro - ERCC1-deficient cells being approximately 1,000 times more sensitive than ERCC1-WT cells - and in vivo. Using transmission electronic microscopy and functional metabolic studies, we found that ERCC1-deficient cells harbor mitochondrial defects. We propose a model where NAD· acts as a regulator of ERCC1-deficient NSCLC cell fitness. These findings open therapeutic opportunities that exploit a yet-undescribed nuclear-mitochondrial synthetic lethal relationship in NSCLC models, and highlight the potential for targeting DNA repair/metabolic crosstalks for cancer therapy.
Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. Excision repair cross-complementation group 1 (ERCC1) deficiency is frequently found in ...non-small-cell lung cancer (NSCLC), making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in the disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house-generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD* and reduced expression of the rate-limiting NAD* biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). We also found reduced NAMPT expression in NSCLC samples with low levels of ERCC1. These metabolic alterations were a primary effect of ERCC1 deficiency, and caused selective exquisite sensitivity to small-molecule NAMPT inhibitors, both in vitro--ERCC1- deficient cells being approximately 1,000 times more sensitive than ERCC1-WT cells--and in vivo. Using transmission electronic microscopy and functional metabolic studies, we found that ERCC1-deficient cells harbor mitochondrial defects. We propose a model where NAD.sup.+ acts as a regulator of ERCC1-deficient NSCLC cell fitness. These findings open therapeutic opportunities that exploit a yet-undescribed nuclear-mitochondrial synthetic lethal relationship in NSCLC models, and highlight the potential for targeting DNA repair/metabolic crosstalks for cancer therapy.
Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. Excision repair cross-complementation group 1 (ERCC1) deficiency is frequently found in ...non-small-cell lung cancer (NSCLC), making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in the disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house-generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). We also found reduced NAMPT expression in NSCLC samples with low levels of ERCC1. These metabolic alterations were a primary effect of ERCC1 deficiency, and caused selective exquisite sensitivity to small-molecule NAMPT inhibitors, both in vitro - ERCC1-deficient cells being approximately 1,000 times more sensitive than ERCC1-WT cells - and in vivo. Using transmission electronic microscopy and functional metabolic studies, we found that ERCC1-deficient cells harbor mitochondrial defects. We propose a model where NAD+ acts as a regulator of ERCC1-deficient NSCLC cell fitness. These findings open therapeutic opportunities that exploit a yet-undescribed nuclear-mitochondrial synthetic lethal relationship in NSCLC models, and highlight the potential for targeting DNA repair/metabolic crosstalks for cancer therapy.
Abstract Molecular targeted therapies (MTTs) have become a major component of modern management of various hematological and solid malignancies. However, some MTTs have been associated with ...cardiotoxicity. MTT-induced cardiovascular side effects include left ventricular systolic dysfunction, heart failure, conduction abnormalities, acute coronary syndrome, and hypertension. One of the most threatening complications of MTT, and notably of angiogenic inhibitors, is QT prolongation with the risk of torsades de pointe and sudden death. The precise incidence of cardiovascular events associated with MTT as well as their reversibility are unknown. Here, we summarize what is known about the cardiotoxicity of MTT, emphasizing MTTs that target tyrosine kinases. We have tried to provide both the basic mechanisms underlying specific cardiotoxicities (such as the interruption of specific signaling pathways leading to cardiomyocyte dysfunction and/or death), and offer guidance regarding the optimal way to detect and treat these cardiotoxicities.
Expression of retinoic acid receptor β (RARβ) and telomerase catalytic subunit (human telomerase reverse transcriptase hTERT) was analyzed in 285 bronchial biopsy specimens from 53 heavy cigarette ...smokers and four former smokers by using in situ hybridization. Of the 191 biopsy specimens that were positive for RARβ, 69% expressed hTERT, whereas only 54% of the 94 RARβ negative biopsy specimens expressed hTERT (P = .014). Because hTERT expression in bronchial tissue has been previously associated with increased risk of lung cancer, the association between RARβ and hTERT expression suggests that RARβ expression may be an indicator of increased risk of lung cancer in heavy smokers.
Abstract The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting ...the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient’s plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.
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