48 results on '"M, Uguen"'
Search Results
2. Asbestos-related lung cancers: A retrospective clinical and pathological study
- Author
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M, Uguen, Dewitte, Jean-Dominique, P, Marcorelles, B, Lodde, R, Pougnet, P, Saliou, Laboratoire d'Études et de Recherche en Sociologie (LABERS), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois des Sciences de l'Homme et de la Société (IBSHS), Université de Brest (UBO), and ALAOUI, MAHEBENA
- Subjects
[SHS.SOCIO]Humanities and Social Sciences/Sociology ,[SHS.SOCIO] Humanities and Social Sciences/Sociology ,[SHS] Humanities and Social Sciences ,ComputingMilieux_MISCELLANEOUS ,[SHS]Humanities and Social Sciences - Abstract
International audience
- Published
- 2017
3. Preclinical evaluation of the abuse potential of Pitolisant, a histamine H3receptor inverse agonist/antagonist compared with Modafinil
- Author
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M Uguen, PM Beardsley, Xavier Ligneau, Jeanne-Marie Lecomte, Perrin David, S Belliard, and J.-C. Schwartz
- Subjects
Pharmacology ,Pitolisant ,Dopaminergic ,Modafinil ,Physical dependence ,Nucleus accumbens ,Conditioned place preference ,chemistry.chemical_compound ,chemistry ,Dopamine ,medicine ,Inverse agonist ,medicine.symptom ,Psychology ,medicine.drug - Abstract
Background and Purpose Pitolisant, a histamine H3 receptor inverse agonist/antagonist is currently under Phase III clinical trials for treatment of excessive daytime sleepiness namely in narcoleptic patients. Its drug abuse potential was investigated using in vivo models in rodents and monkeys and compared with those of Modafinil, a psychostimulant currently used in the same indications. Experimental Approach Effects of Pitolisant on dopamine release in the nucleus accumbens, on spontaneous and cocaine-induced locomotion, locomotor sensitization were monitored. It was also tested in three standard drug abuse tests i.e. conditioned place preference in rats, self-administration in monkeys and cocaine discrimination in mice as well as in a physical dependence model. Key Results Pitolisant did not elicit any significant changes in dopaminergic indices in rat nucleus accumbens whereas Modafinil increased dopamine release. In rodents, Pitolisant was without any effect on locomotion and reduced the cocaine-induced hyperlocomotion. In addition, no locomotor sensitization and no conditioned hyperlocomotion were evidenced with this compound in rats whereas significant effects were elicited by Modafinil. Finally, Pitolisant was devoid of any significant effects in the three standard drug abuse tests (including self-administration in monkeys) and in the physical dependence model. Conclusions and Implications No potential drug abuse liability for Pitolisant was evidenced in various in vivo rodent and primate models, whereas the same does not seem so clear in the case of Modafinil.
- Published
- 2013
4. Dysbaric osteonecrosis among professional divers: a literature review
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M, Uguen, R, Pougnet, A, Uguen, B, Loddé, and J D, Dewitte
- Subjects
Occupational Diseases ,Observational Studies as Topic ,Cross-Sectional Studies ,Risk Factors ,Diving ,Osteonecrosis ,Humans ,Femur ,Humerus ,Prognosis - Abstract
Dysbaric osteonecrosis (DON) continues to be a significant occupational hazard that has significant medical and social consequences for professional divers. This review aims to evaluate the prevalence and risk factors of DON among professional divers and to summarize the scientific knowledge regarding distribution of the lesions as well as disease prognosis and treatment.A literature review using the Medline database.The prevalence of DON varies between 0 and 70.6% in professional divers, and its prevalence is highest in Turkey, Hawaii, Korea and Japan but is dependent on activity and medical monitoring. The risk of DON is very low for military divers who strictly obey the decompression rules and who undergo periodic medical examination. DON pre- dominately occurs in the proximal part of the femur and humerus. In a majority of cases, DON will progress despite the absence of further dysbaric exposure.The pathophysiology of the disease is incompletely understood and other etiological factors are perhaps being overlooked.
- Published
- 2015
5. Preclinical evaluation of the abuse potential of Pitolisant, a histamine H₃ receptor inverse agonist/antagonist compared with Modafinil
- Author
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M, Uguen, D, Perrin, S, Belliard, X, Ligneau, P M, Beardsley, J M, Lecomte, and J C, Schwartz
- Subjects
Male ,Behavior, Animal ,Dose-Response Relationship, Drug ,Drug Inverse Agonism ,Dopamine ,Dopaminergic Neurons ,Drug Evaluation, Preclinical ,Histamine Antagonists ,Modafinil ,Drugs, Investigational ,Wakefulness-Promoting Agents ,Motor Activity ,Macaca mulatta ,Research Papers ,Nucleus Accumbens ,Rats ,Behavior, Addictive ,Histamine Agonists ,Mice ,Piperidines ,Animals ,Receptors, Histamine H3 ,Central Nervous System Stimulants ,Benzhydryl Compounds ,Drug Antagonism - Abstract
Pitolisant, a histamine H₃ receptor inverse agonist/antagonist is currently under Phase III clinical trials for treatment of excessive daytime sleepiness namely in narcoleptic patients. Its drug abuse potential was investigated using in vivo models in rodents and monkeys and compared with those of Modafinil, a psychostimulant currently used in the same indications.Effects of Pitolisant on dopamine release in the nucleus accumbens, on spontaneous and cocaine-induced locomotion, locomotor sensitization were monitored. It was also tested in three standard drug abuse tests i.e. conditioned place preference in rats, self-administration in monkeys and cocaine discrimination in mice as well as in a physical dependence model.Pitolisant did not elicit any significant changes in dopaminergic indices in rat nucleus accumbens whereas Modafinil increased dopamine release. In rodents, Pitolisant was without any effect on locomotion and reduced the cocaine-induced hyperlocomotion. In addition, no locomotor sensitization and no conditioned hyperlocomotion were evidenced with this compound in rats whereas significant effects were elicited by Modafinil. Finally, Pitolisant was devoid of any significant effects in the three standard drug abuse tests (including self-administration in monkeys) and in the physical dependence model.No potential drug abuse liability for Pitolisant was evidenced in various in vivo rodent and primate models, whereas the same does not seem so clear in the case of Modafinil.
- Published
- 2012
6. Potent and Selective SETDB1 Covalent Negative Allosteric Modulator Reduces Methyltransferase Activity in Cells.
- Author
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Uguen M, Shell DJ, Silva M, Deng Y, Li F, Szewczyk MM, Yang K, Zhao Y, Stashko MA, Norris-Drouin JL, Waybright JM, Beldar S, Rectenwald JM, Mordant AL, Webb TS, Herring LE, Arrowsmith CH, Ackloo S, Gygi SP, McGinty RK, Barsyte-Lovejoy D, Liu P, Halabelian L, James LI, Pearce KH, and Frye SV
- Abstract
A promising drug target, SETDB1, is a dual Kme reader and methyltransferase, which has been implicated in cancer and neurodegenerative disease progression. To help understand the role of the triple Tudor domain (3TD) of SETDB1, its Kme reader, we first identified a low micromolar small molecule ligand, UNC6535, which occupies simultaneously both the TD2 and TD3 reader binding sites. Further optimization led to the discovery of UNC10013, the first covalent 3TD ligand targeting Cys385 of SETDB1. UNC10013 is potent with a k
inact /KI of 1.0 x 106 M-1 s-1 and demonstrated proteome-wide selectivity. In cells, negative allosteric modulation of SETDB1-mediated Akt methylation was observed after treatment with UNC10013. Therefore, UNC10013 is a potent, selective and cell-active covalent ligand for the 3TD of SETDB1, demonstrating negative allosteric modulator properties and making it a promising tool to study the biological role of SETDB1 in disease progression.- Published
- 2024
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7. Phase 3 randomized COMMODORE 1 trial: Crovalimab versus eculizumab in complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria.
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Scheinberg P, Clé DV, Kim JS, Nur E, Yenerel MN, Barcellini W, Bonito D, Giai V, Hus M, Lee Y, Lekue CB, Panse J, Ueda Y, Buatois S, Gentile B, Kiialainen A, Patel H, Sreckovic S, Uguen M, Edwards J, Nagy Z, and Kulasekararaj AG
- Subjects
- Humans, Female, Male, Middle Aged, Adult, Aged, Complement C5 antagonists & inhibitors, Treatment Outcome, Hemoglobinuria, Paroxysmal drug therapy, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized administration & dosage, Complement Inactivating Agents therapeutic use, Complement Inactivating Agents adverse effects, Complement Inactivating Agents administration & dosage
- Abstract
Crovalimab, a novel C5 inhibitor, allows for low-volume, every-4- week, subcutaneous self-administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight-based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT-Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty-nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24-week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab-treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab-treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor-naive patients, these data support crovalimab's favorable benefit-risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)
- Published
- 2024
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8. The tolerance of a keystone ecosystem engineer to extreme heat stress is hampered by microplastic leachates.
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Uguen M, Gaudron SM, Nicastro KR, Zardi GI, Spilmont N, Henry S, and Seuront L
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- Animals, Microplastics, Plastics, Ecosystem, Heat-Shock Response, Extreme Heat, Mytilus edulis, Water Pollutants, Chemical
- Abstract
Plastic pollution and ongoing climatic changes exert considerable pressure on coastal ecosystems. Unravelling the combined effects of these two threats is essential to management and conservation actions to reduce the overall environmental risks. We assessed the capacity of a coastal ecosystem engineer, the blue mussel Mytilus edulis , to cope with various levels of aerial heat stress (20, 25, 30 and 35°C) after an exposure to substances leached from beached and virgin low-density polyethylene pellets. Our results revealed a significant interaction between temperature and plastic leachates on mussel survival rates. Specifically, microplastic leachates had no effect on mussel survival at 20, 25 and 30°C. In turn, mussel survival rates significantly decreased at 35°C, and this decrease was even more significant following an exposure to leachates from beached pellets; these pellets had a higher concentration of additives compared to the virgin ones, potentially causing a bioenergetic imbalance. Our results stress the importance of adopting integrated approaches combining the effects of multiple environmental threats on key marine species to understand and mitigate their potential synergistic effects on ecosystem dynamics and resilience in the face of the changing environment.
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- 2024
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9. Advancing drug development in pediatric oncology, a focus on cancer biology and targeted therapies: iMATRIX platform.
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Uguen M, Hilton M, Farid-Kapadia M, Datye A, Chohan S, Carlucci C, Dixon M, Elze M, Chen Y, Cheung KWK, Sane R, Zheng M, and Choi Y
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- Humans, Child, Drug Development, Biology, Medical Oncology methods, Neoplasms drug therapy
- Abstract
With the development of novel treatment therapies as well as evolving and innovative approaches to conduct clinical trials, the landscape of pediatric oncology drug development has dramatically changed in recent years. Despite this change, approvals for new drugs and labeling updates to ensure availability of proper treatment for pediatric patients with cancer remain slow. The context of drug development in pediatric tumors has also changed with regulatory initiatives in the US and Europe, creating a great need for faster development of novel drugs. Today, conventional study designs have been replaced or complemented by novel clinical trial designs, such as master protocols and platform trials, to optimize cancer drug development and enable faster regulatory approval. The iMATRIX platform is a mechanism-of-action (MOA)-based phase 1/2 trial framework for concurrently studying multiple molecules across a range of relevant pediatric tumor types, taking into account the biology of each pediatric tumor type. Six studies have been conducted, ongoing, or planned on the iMATRIX platform - investigating atezolizumab, cobimetinib, entrectinib, idasanutlin, alectinib, and glofitamab. A brief overview of study designs and characteristics are shared in this article, along with learnings from them.
- Published
- 2023
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10. Safety and efficacy of zinpentraxin alfa as monotherapy or in combination with ruxolitinib in myelofibrosis: stage I of a phase II trial.
- Author
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Verstovsek S, Foltz L, Gupta V, Hasserjian R, Manshouri T, Mascarenhas J, Mesa R, Pozdnyakova O, Ritchie E, Veletic I, Gamel K, Hamidi H, Han L, Higgins B, Trunzer K, Uguen M, Wang D, El-Galaly TC, Todorov B, and Gotlib J
- Subjects
- Humans, Anemia, Fibrosis, Treatment Outcome, Drug Therapy, Combination adverse effects, Primary Myelofibrosis diagnosis, Primary Myelofibrosis drug therapy, Recombinant Proteins adverse effects
- Abstract
Pentraxin 2 (PTX-2; serum amyloid P component), a circulating endogenous regulator of the inflammatory response to tissue injury and fibrosis, is reduced in patients with myelofibrosis (MF). Zinpentraxin alfa (RO7490677, PRM-151) is a recombinant form of PTX-2 that has shown preclinical antifibrotic activity and no dose-limiting toxicities in phase I trials. We report results from stage 1 of a phase II trial of zinpentraxin alfa in patients with intermediate-1/2 or high-risk MF. Patients (n=27) received intravenous zinpentraxin α weekly (QW) or every 4 weeks (Q4W), as monotherapy or an additional therapy for patients on stable-dose ruxolitinib. The primary endpoint was overall response rate (ORR; investigatorassessed) adapted from International Working Group-Myeloproliferative Neoplasms Research and Treatment criteria. Secondary endpoints included modified Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) change, bone marrow (BM) MF grade reduction, pharmacokinetics, and safety. ORR at week 24 was 33% (n=9/27) and varied across individual cohorts (QW: 38% [3/8]; Q4W: 14% [1/7]; QW+ruxolitinib: 33% [2/6]; Q4W+ruxolitinib: 50% [3/6]). Five of 18 evaluable patients (28%) experienced a ≥50% reduction in MPN-SAF TSS, and six of 17 evaluable patients (35%) had a ≥1 grade improvement from baseline in BM fibrosis at week 24. Most treatment-emergent adverse events (AE) were grade 1-2, most commonly fatigue. Among others, anemia and thrombocytopenia were infrequent (n=3 and n=1, respectively). Treatment-related serious AE occurred in four patients (15%). Overall, zinpentraxin alfa showed evidence of clinical activity and tolerable safety as monotherapy and in combination with ruxolitinib in this open-label, non-randomized trial (clinicaltrials gov. Identifier: NCT01981850).
- Published
- 2023
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11. Size-dependent response of the mussel collective behaviour to plastic leachates and predator cues.
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Uguen M, Gaudron SM, Nicastro KR, Zardi GI, Spilmont N, and Seuront L
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- Animals, Ecosystem, Plastics, Mass Behavior, Cues, Mytilus edulis physiology, Brachyura physiology
- Abstract
Both individual and collective anti-predator behaviours are essential for the survival of many species. This is particularly true for ecosystem engineers such as intertidal mussels, which through their collective behaviour create novel habitats for a range of organisms and biodiversity hotspots. However, contaminants may disrupt these behaviours and consequently indirectly affect exposure to predation risk at the population level. Among these, plastic litter is a major and ubiquitous contaminant of the marine environment. Here, we assessed the impact of microplastic (MP) leachates of the most produced plastic polymer, polypropylene (PlasticsEurope, 2022), at a high but locally relevant concentration (i.e. ca. 12 g L
-1 ) on the collective behaviours and anti-predator responses of both small and large Mytilus edulis mussels. Indeed, in contrast to large mussels, small ones reacted to MP leachates, showing a taxis towards conspecifics and stronger aggregations. All mussels reacted to the chemical cues of the predatory crab, Hemigrapsus sanguineus, but with two different collective anti-predator behaviours. Small mussels only showed a taxis towards conspecifics when exposed to predator cues. This response was also found in large ones with a tendency to form more strongly bound aggregations and a considerable reduced activity, i.e. they significantly delayed their time to start to form aggregations and decreased their gross distance. These anti-predator behaviours were respectively inhibited and impaired in small and large mussels by MP leachates. The observed collective behavioural changes may reduce individual fitness by enhancing predation risk, particularly in small mussels that are the crab H. sanguineus's favourite preys. Given the key role of mussels as ecosystem engineers, our observations suggest that plastic pollution may have implication on M. edulis at the species level, but also enhancing a cascading effect towards a higher level of organisation such as population, community and ultimately structure and function of intertidal ecosystem., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)- Published
- 2023
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12. SETDB1 Triple Tudor Domain Ligand, ( R , R )-59, Promotes Methylation of Akt1 in Cells.
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Uguen M, Deng Y, Li F, Shell DJ, Norris-Drouin JL, Stashko MA, Ackloo S, Arrowsmith CH, James LI, Liu P, Pearce KH, and Frye SV
- Subjects
- Ligands, Methylation, Tudor Domain, Histone-Lysine N-Methyltransferase metabolism, PR-SET Domains
- Abstract
Increased expression and hyperactivation of the methyltransferase SET domain bifurcated 1 (SETDB1) are commonly observed in cancer and central nervous system disorders. However, there are currently no reported SETDB1-specific methyltransferase inhibitors in the literature, suggesting that this is a challenging target. Here, we disclose that the previously reported small-molecule ligand for SETDB1's triple tudor domain, ( R , R )-59, is unexpectedly able to increase SETDB1 methyltransferase activity both in vitro and in cells. Specifically, ( R , R )-59 promotes in vitro SETDB1-mediated methylation of lysine 64 of the protein kinase Akt1. Treatment with ( R , R )-59 also increased Akt1 threonine 308 phosphorylation and activation, a known consequence of Akt1 methylation, resulting in stimulated cell proliferation in a dose-dependent manner. ( R , R )-59 is the first SETDB1 small-molecule positive activator for the methyltransferase activity of this protein. Mechanism of action studies show that full-length SETDB1 is required for significant in vitro methylation of an Akt1-K64 peptide and that this activity is stimulated by ( R , R )-59 primarily through an increase in catalytic activity rather than a change in S -adenosyl methionine binding.
- Published
- 2023
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13. SETDB1 Triple Tudor Domain Ligand, ( R,R )-59, Promotes Methylation of Akt1 in Cells.
- Author
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Uguen M, Deng Y, Li F, Shell DJ, Norris-Drouin JL, Stashko MA, Ackloo S, Arrowsmith CH, James LI, Liu P, Pearce KH, and Frye SV
- Abstract
Increased expression and hyperactivation of the methyltransferase SETDB1 are commonly observed in cancer and central nervous system disorders. However, there are currently no reported SETDB1-specific methyltransferase inhibitors in the literature, suggesting this is a challenging target. Here, we disclose that the previously reported small-molecule ligand for SETDB1's Triple Tudor Domain, ( R,R )-59, is unexpectedly able to increase SETDB1 methyltransferase activity both in vitro and in cells. Specifically, ( R,R )-59 promotes in vitro SETDB1-mediated methylation of lysine 64 of the protein kinase Akt1. Treatment with ( R,R )-59 also increased Akt1 threonine 308 phosphorylation and activation, a known consequence of Akt1 methylation, resulting in stimulated cell proliferation in a dose-dependent manner. ( R,R )-59 is the first SETDB1 small-molecule positive activator for the methyltransferase activity of this protein. Mechanism of action studies show that full-length SETDB1 is required for significant in vitro methylation of an Akt1-K64 peptide, and that this activity is stimulated by ( R,R )-59 primarily through an increase in catalytic activity rather than a change in SAM binding.
- Published
- 2023
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14. The Histopathological "Placentitis Triad" Is Specific for SARS-CoV-2 Infection, and Its Acute Presentation Can Be Associated with Poor Fetal Outcome.
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Remoué A, Suazo Y, Uguen M, Uguen A, Marcorelles P, and de Moreuil C
- Abstract
(1) Background: Placental histological lesions reported in relation with SARS-CoV-2 infection are various, with potential consequences such as fetal growth retardation, prematurity or stillbirth/neonatal death. We report here on a placental pathological association which could be specific for SARS-CoV-2 infection and associated with poor fetal outcome; (2) Methods: We collected all the placental pathological examinations performed in Brest University Hospital (France) since the beginning of COVID-19 pandemic with a known maternal SARS-CoV-2 infection and a poor pregnancy outcome. In these cases, we described the pathological lesions and we searched for these lesions in a large series of placentas collected and examined in the same institution before the SARS-CoV-2 pandemic; (3) Results: Three cases with severe fetal outcome (tardive abortion, prematurity, neonatal death), from the first to the third trimesters of pregnancy, were included. The three cases showed features of massive and acute "placentitis triad" consisting in massive perivillous fibrin deposition, sub-acute intervillositis and trophoblastic necrosis. This association was not encountered in any of 8857 placentas analyzed during the period between 2002 and 2012 in our institution; (4) Conclusions: The "placentitis triad" appears to be specific for SARS-CoV-2 infection and, in case of massive and acute presentation, could result in poor fetal outcome.
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- 2023
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15. Discovery of hit compounds for methyl-lysine reader proteins from a target class DNA-encoded library.
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Shell DJ, Rectenwald JM, Buttery PH, Johnson RL, Foley CA, Guduru SKR, Uguen M, Rubiano JS, Zhang X, Li F, Norris-Drouin JL, Axtman M, Brian Hardy P, Vedadi M, Frye SV, James LI, and Pearce KH
- Subjects
- DNA genetics, Lysine, Epigenesis, Genetic
- Abstract
Methyl-lysine (Kme) reader domains are prevalent in chromatin regulatory proteins which bind post-translational modification sites to recruit repressive and activating factors; therefore, these proteins play crucial roles in cellular signaling and epigenetic regulation. Proteins that contain Kme domains are implicated in various diseases, including cancer, making them attractive therapeutic targets for drug and chemical probe discovery. Herein, we report on expanding the utility of a previously reported, Kme-focused DNA-encoded library (DEL), UNCDEL003, as a screening tool for hit discovery through the specific targeting of Kme reader proteins. As an efficient method for library generation, focused DELs are designed based on structural and functional features of a specific class of proteins with the intent of novel hit discovery. To broadly assess the applicability of our library, UNCDEL003 was screened against five diverse Kme reader protein domains (53BP1 TTD, KDM7B JmjC-PHD, CDYL2 CD, CBX2 CD, and LEDGF PWWP) with varying structures and functions. From these screening efforts, we identified hit compounds which contain unique chemical scaffolds distinct from previously reported ligands. The selected hit compounds were synthesized off-DNA and confirmed using primary and secondary assays and assessed for binding selectivity. Hit compounds from these efforts can serve as starting points for additional development and optimization into chemical probes to aid in further understanding the functionality of these therapeutically relevant proteins., Competing Interests: Declaration of Conflicting Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)
- Published
- 2022
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16. A whale of a plastic tale: A plea for interdisciplinary studies to tackle micro- and nanoplastic pollution in the marine realm.
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Seuront L, Zardi GI, Uguen M, Bouchet VMP, Delaeter C, Henry S, Spilmont N, and Nicastro KR
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- Animals, Environmental Monitoring methods, Humans, Interdisciplinary Studies, Microplastics, Polymers, Whales, Plastics chemistry, Water Pollutants, Chemical analysis
- Abstract
Plastic is one of the most ubiquitous sources of both contamination and pollution of the Anthropocene, and accumulates virtually everywhere on the planet. As such, plastic threatens the environment, the economy and human well-being globally. The related potential threats have been identified as a major global conservation issue and a key research priority. As a consequence, plastic pollution has become one of the most prolific fields of research in research areas including chemistry, physics, oceanography, biology, ecology, ecotoxicology, molecular biology, sociology, economy, conservation, management, and even politics. In this context, one may legitimately expect plastic pollution research to be highly interdisciplinary. However, using the emerging topic of microplastic and nanoplastic leachate (i.e., the desorption of molecules that are adsorbed onto the surface of a polymer and/or absorbed into the polymer matrix in the absence of plastic ingestion) in the ocean as a case study, we argue that this is still far from being the case. Instead, we highlight that plastic pollution research rather seems to remain structured in mostly isolated monodisciplinary studies. A plethora of analytical methods are now available to qualify and quantify plastic monomers, polymers and the related additives. We nevertheless show though a survey of the literature that most studies addressing the effects of leachates on marine organisms essentially still lack of a quantitative assessment of the chemical nature and content of both plastic items and their leachates. In the context of the ever-increasing research effort devoted to assess the biological and ecological effects of plastic waste, we subsequently argue that the lack of a true interdisciplinary approach is likely to hamper the development of this research field. We finally introduce a roadmap for future research which has to evolve through the development of a sound and systematic ability to chemically define what we biologically compare., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)
- Published
- 2022
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17. Microplastic leachates disrupt the chemotactic and chemokinetic behaviours of an ecosystem engineer (Mytilus edulis).
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Uguen M, Nicastro KR, Zardi GI, Gaudron SM, Spilmont N, Akoueson F, Duflos G, and Seuront L
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- Animals, Ecosystem, Microplastics, Plastics chemistry, Polypropylenes, Brachyura, Mytilus, Mytilus edulis physiology, Water Pollutants, Chemical analysis, Water Pollutants, Chemical toxicity
- Abstract
The massive contamination of the environment by plastics is an increasing global scientific and societal concern. Knowing whether and how these pollutants affect the behaviour of keystone species is essential to identify environmental risks effectively. Here, we focus on the effect of plastic leachates on the behavioural response of the common blue mussel Mytilus edulis, an ecosystem engineer responsible for the creation of biogenic structures that modify the environment and provide numerous ecosystem functions and services. Specifically, we assess the effect of virgin polypropylene beads on mussels' chemotactic (i.e. a directional movement in response to a chemical stimulus) and chemokinetic (i.e. a non-directional change in movement properties such as speed, distance travelled or turning frequency in response to a chemical stimulus) responses to different chemical cues (i.e. conspecifics, injured conspecifics and a predator, the crab Hemigrapsus sanguineus). In the presence of predator cues, individual mussels reduced both their gross distance and speed, changes interpreted here as an avoidance behaviour. When exposed to polypropylene leachates, mussels moved less compared to control conditions, regardless of the cues tested. Additionally, in presence of crab cues with plastic leachates, mussels significantly changed the direction of movement suggesting a leachate-induced loss of their negative chemotaxis response. Taken together, our results indicate that the behavioural response of M. edulis is cue-specific and that its anti-predator behaviour as well as its mobility are impaired when exposed to microplastic leachates, potentially affecting the functioning of the ecosystem that the species supports., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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18. Untreated bleeds in people with hemophilia A in a noninterventional study and intrapatient comparison after initiating emicizumab in HAVEN 1-3.
- Author
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Callaghan MU, Asikanius E, Lehle M, Oldenburg J, Mahlangu J, Uguen M, Chebon S, Kruse-Jarres R, Jiménez-Yuste V, Shima M, Trask P, Kempton CL, Kessler CM, Levy GG, and Peyvandi F
- Abstract
Background: Bleeding in people with hemophilia A can be life threatening, and intra-articular bleeds can result in joint damage. Most clinical studies focus on treated bleeds, while bleeds not treated with coagulation factor(s) (untreated bleeds) are underreported., Objectives: We assessed the incidence of untreated bleeds during a noninterventional study (NIS) wherein people with hemophilia A, with or without factor VIII (FVIII) inhibitors, were managed according to standard practice., Patients/methods: Using the Bleed and Medication Questionnaire, we prospectively collected data from three cohorts: Cohort A, adults/adolescents (age ≥12 years) with FVIII inhibitors; Cohort B, children (aged <12 years) with FVIII inhibitors; Cohort C, adults/adolescents without FVIII inhibitors. Untreated bleeds were analyzed for site, frequency, and etiology of bleeding and compared with those during emicizumab prophylaxis in the same individuals after transferring to a Phase III HAVEN trial., Results: In the 221 participants enrolled in the NIS (Cohort A, n = 103; Cohort B, n = 24; Cohort C, n = 94), the incidence of untreated bleeds was approximately 40% of all bleeds in people with FVIII inhibitors and 26.2% in adolescents/adults without inhibitors. Approximately 70% of treated bleeds and approximately 54% of untreated bleeds in adults/adolescents were in joints. Untreated joint bleeds were less common (7.1%) in children. Overall, intra-individual comparisons showed reduced treated/untreated bleeds following transition from standard to emicizumab prophylaxis., Conclusion: A significant proportion of bleeding events are untreated in people with hemophilia A. There is a need to further understand why bleeds remain untreated and to capture such events in clinical studies., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)
- Published
- 2022
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19. Build-Couple-Transform: A Paradigm for Lead-like Library Synthesis with Scaffold Diversity.
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Uguen M, Davison G, Sprenger LJ, Hunter JH, Martin MP, Turberville S, Watt JE, Golding BT, Noble MEM, Stewart HL, and Waring MJ
- Subjects
- High-Throughput Screening Assays, Small Molecule Libraries chemistry
- Abstract
High-throughput screening provides one of the most common ways of finding hit compounds. Lead-like libraries, in particular, provide hits with compatible functional groups and vectors for structural elaboration and physical properties suitable for optimization. Library synthesis approaches can lead to a lack of chemical diversity because they employ parallel derivatization of common building blocks using single reaction types. We address this problem through a "build-couple-transform" paradigm for the generation of lead-like libraries with scaffold diversity. Nineteen transformations of a 4-oxo-2-butenamide scaffold template were optimized, including 1,4-cyclizations, 3,4-cyclizations, reductions, and 1,4-additions. A pool-transformation approach efficiently explored the scope of these transformations for nine different building blocks and synthesized a >170-member library with enhanced chemical space coverage and favorable drug-like properties. Screening revealed hits against CDK2. This work establishes the build-couple-transform concept for the synthesis of lead-like libraries and provides a differentiated approach to libraries with significantly enhanced scaffold diversity.
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- 2022
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20. Microwave-assisted synthesis of 4-oxo-2-butenoic acids by aldol-condensation of glyoxylic acid.
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Uguen M, Gai C, Sprenger LJ, Liu H, Leach AG, and Waring MJ
- Abstract
4-Oxobutenoic acids are useful as biologically active species and as versatile intermediates for further derivatisation. Currently, routes to their synthesis can be problematic and lack generality. Reaction conditions for the synthesis of 4-oxo-2-butenoic acid by microwave-assisted aldol-condensation between methyl ketone derivatives and glyoxylic acid have been developed. They provide the desired products in moderate to excellent yields for a wide range of substrates, by applying a simple procedure to accessible starting materials. The investigation revealed different conditions are required depending on the nature of the methylketone substituent, with aryl derivatives proceeding best using tosic acid and aliphatic substrates reacting best with pyrrolidine and acetic acid. This substituent effect is rationalised by frontier orbital calculations. Overall, this work provides methods for synthesis of 4-oxo-butenoic acids across a broad range of substrates., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)
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- 2021
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21. Pitolisant, a wake-promoting agent devoid of psychostimulant properties: Preclinical comparison with amphetamine, modafinil, and solriamfetol.
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Krief S, Berrebi-Bertrand I, Nagmar I, Giret M, Belliard S, Perrin D, Uguen M, Robert P, Lecomte JM, Schwartz JC, Finance O, and Ligneau X
- Subjects
- 3,4-Dihydroxyphenylacetic Acid metabolism, Adrenergic Uptake Inhibitors pharmacology, Animals, Corpus Striatum metabolism, Disorders of Excessive Somnolence etiology, Dopamine metabolism, Dopamine Plasma Membrane Transport Proteins drug effects, Dopamine Plasma Membrane Transport Proteins metabolism, Dopamine Uptake Inhibitors pharmacology, Drug Evaluation, Preclinical, Drug Inverse Agonism, Histamine Antagonists pharmacology, Mice, Narcolepsy drug therapy, Neostriatum drug effects, Neostriatum metabolism, Norepinephrine Plasma Membrane Transport Proteins drug effects, Norepinephrine Plasma Membrane Transport Proteins metabolism, Nucleus Accumbens drug effects, Nucleus Accumbens metabolism, Phenylalanine pharmacology, Receptors, Histamine H3, Sleep Apnea, Obstructive complications, Amphetamine pharmacology, Carbamates pharmacology, Corpus Striatum drug effects, Disorders of Excessive Somnolence drug therapy, Feeding Behavior drug effects, Locomotion drug effects, Modafinil pharmacology, Phenylalanine analogs & derivatives, Piperidines pharmacology, Wakefulness-Promoting Agents pharmacology
- Abstract
Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models., (© 2021 Bioprojet Biotech. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)
- Published
- 2021
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22. Health-related quality of life and caregiver burden of emicizumab in children with haemophilia A and factor VIII inhibitors-Results from the HAVEN 2 study.
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Mancuso ME, Mahlangu J, Sidonio R Jr, Trask P, Uguen M, Chang T, Shima M, Young G, Oldenburg J, and von Mackensen S
- Subjects
- Adolescent, Antibodies, Bispecific pharmacology, Antibodies, Monoclonal, Humanized pharmacology, Caregiver Burden, Child, Child, Preschool, Female, Humans, Infant, Male, Patient Reported Outcome Measures, Antibodies, Bispecific therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Factor VIII antagonists & inhibitors, Hemophilia A drug therapy, Quality of Life psychology
- Abstract
Introduction: Persons with haemophilia A (PwHA) with factor (F)VIII inhibitors, including children, have impaired health-related quality of life (HRQoL). The HAVEN 2 study (NCT027955767) of paediatric PwHA with FVIII inhibitors demonstrated that subcutaneous emicizumab prophylaxis resulted in low annualizedbleed rates., Aim: We assessed the impact of emicizumab prophylaxis on the HRQoL of children and their caregivers participating in HAVEN 2., Methods: Children aged 8-11 years self-reported HRQoL using the Haemophilia-Specific Quality of Life Assessment Instrument for Children and Adolescents Short Form (Haemo-QoL SF II). Caregivers of children aged 0-11 years completed the Adapted Inhibitor-Specific Quality of Life Assessment with Aspects of Caregiver Burden. All scores were transformed to a 0-100 scale, where lower scores reflect a better HRQoL. The number of missed days from school/day care and hospitalizations was also recorded., Results: In HAVEN 2 (n = 88), the median age was 6.5 years (range: 1-15 years); 85 participants were aged < 12 years and included in this analysis, and 34 participants were aged 8-11 years, thereby eligible to complete the Haemo-QoL SF II questionnaire. The mean (standard deviation, n) baseline Haemo-QoL SF II 'Total' score was 30.2 (14.9, 30), indicating moderate impairment; with emicizumab, mean score decreased by -9.62 (7.73, 17) points to 23.0 (13.93, 20) by Week 49. The most improved domains were 'Sports & School' and 'Physical Health'. Caregivers reported similar improvements., Conclusion: Prophylactic emicizumab is accompanied by substantial and sustained improvements in HRQoL of paediatric PwHA with FVIII inhibitors and their caregivers., (© 2020 The Authors. Haemophilia published by John Wiley & Sons Ltd.)
- Published
- 2020
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23. Evaluation of posaconazole antifungal prophylaxis in reducing the incidence of invasive aspergillosis in patients with acute myeloid leukemia.
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Le Clech L, Uguen M, Quinio D, Nevez G, Couturier MA, Ianotto JC, Berthou C, Guillerm G, Le Bars H, Payan C, Narbonne V, Baron R, and Saliou P
- Subjects
- Adult, Aerosols, Air Filters, Air Microbiology, Air Pollution, Indoor, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Aspergillosis epidemiology, Aspergillus drug effects, Aspergillus isolation & purification, Aspergillus physiology, Combined Modality Therapy, Environmental Exposure, Febrile Neutropenia complications, Female, Filtration, France, Hematopoietic Stem Cell Transplantation, Hospital Design and Construction, Hospitals, Teaching, Humans, Incidence, Invasive Fungal Infections epidemiology, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Prospective Studies, Retrospective Studies, Spores, Fungal, Antifungal Agents therapeutic use, Aspergillosis prevention & control, Invasive Fungal Infections prevention & control, Leukemia, Myeloid, Acute complications, Triazoles therapeutic use
- Abstract
Purpose of the Study: Invasive aspergillosis (IA) is the most prevalent invasive fungal disease (IFD) in neutropenic patients. Environment is the main source of Aspergillus spores aerosolization especially during building construction. International guidelines recommend mechanical protection during hospital building works; otherwise the use of antifungal prophylaxis is not clearly indicated. Our objective was to determine the efficacy of antifungal prophylaxis by posaconazole on IA incidence in acute myeloid leukemia population and to analyse the benefit of this prophylaxis and HEPA-filters during hospital buildings works., Patients and Methods: We included patients treated for acute myeloid leukemia at Brest teaching hospital from January 2009 to December 2015. We compared incidence of IA in the group treated by posaconazole from 2012 to 2015 to the incidence of IA in the first group who did not receive antifungal prophylaxis (from 2009 to 2011). The one-year overall survival was also analyzed using the Kaplan-Meier method., Results: 245 patients were enrolled including 151 treated with posaconazole. 23 IA were diagnosed between 2009 and 2011 (without antifungal prophylaxis), then 31 between 2012 and 2015 (with posaconazole) without statistical difference between the incidence densities (0.34 per 100 hospitalization-days vs. 0.30 per 100 hospitalization-days, p = 0.71). Incidence density of IA increased during building works (2.40 per 100 hospitalization-days vs. 0.28 per 100 hospitalization-days, p < 0.0001). The incidence density of IA significantly decreased during construction periods when posaconazole prophylaxis was used (1.59 per 100 hospitalization-days vs. 4.87 per 100 hospitalization-days p < 0.0001)., Conclusion: Our study suggests, for the first time, the interest of antifungal prophylaxis in addition to HEPA filtration in prevention of IA during hospital building works., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
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24. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors.
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Young G, Liesner R, Chang T, Sidonio R, Oldenburg J, Jiménez-Yuste V, Mahlangu J, Kruse-Jarres R, Wang M, Uguen M, Doral MY, Wright LY, Schmitt C, Levy GG, Shima M, and Mancuso ME
- Subjects
- Adolescent, Antibodies, Bispecific administration & dosage, Antibodies, Bispecific adverse effects, Antibodies, Bispecific pharmacokinetics, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized pharmacokinetics, Child, Child, Preschool, Factor VIII antagonists & inhibitors, Factor VIII immunology, Female, Hemophilia A immunology, Humans, Infant, Isoantibodies blood, Isoantibodies immunology, Male, Quality of Life, Treatment Outcome, Antibodies, Bispecific therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Hemophilia A complications, Hemophilia A drug therapy, Hemorrhage etiology, Hemorrhage prevention & control
- Abstract
Emicizumab, a bispecific humanized monoclonal antibody, bridges activated factor IX (FIX) and FX to restore the function of missing activated FVIII in hemophilia A. Emicizumab prophylaxis in children with hemophilia A and FVIII inhibitors was investigated in a phase 3 trial (HAVEN 2). Participants, previously receiving episodic/prophylactic bypassing agents (BPAs), were treated with subcutaneous emicizumab: 1.5 mg/kg weekly (group A), 3 mg/kg every 2 weeks (group B), or 6 mg/kg every 4 weeks (group C). Pharmacokinetics, safety, and efficacy (including an intraindividual comparison of participants from a noninterventional study) were evaluated. Eighty-five participants aged <12 years were enrolled. In group A (n = 65), the annualized rate of treated bleeding events (ABRs) was 0.3 (95% confidence interval [CI], 0.17-0.50), and 77% had no treated bleeding events. Intraindividual comparison of 15 participants who previously took BPA prophylaxis showed that emicizumab prophylaxis reduced the ABR by 99% (95% CI, 97.4-99.4). In groups B (n = 10) and C (n = 10), ABRs were 0.2 (95% CI, 0.03-1.72) and 2.2 (95% CI, 0.69-6.81), respectively. The most frequent adverse events were nasopharyngitis and injection-site reactions; no thrombotic events occurred. Two of 88 participants developed antidrug antibodies (ADAs) with neutralizing potential, that is, associated with decreased emicizumab plasma concentrations: 1 experienced loss of efficacy, and, in the other, ADAs disappeared over time without intervention or breakthrough bleeding. All other participants achieved effective emicizumab plasma concentrations, regardless of the treatment regimen. Emicizumab prophylaxis has been shown to be a highly effective novel medication for children with hemophilia A and inhibitors. This trial was registered at www.clinicaltrials.gov as #NCT02795767., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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25. The p16-Ki-67-HMB45 Immunohistochemistry Scoring System is Highly Concordant With the Fluorescent In Situ Hybridization Test to Differentiate Between Melanocytic Nevi and Melanomas.
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Uguen A, Uguen M, Guibourg B, Talagas M, Marcorelles P, and De Braekeleer M
- Subjects
- Biomarkers, Tumor metabolism, Chromosome Disorders, Cyclin-Dependent Kinase Inhibitor p16 genetics, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Diagnosis, Differential, Early Detection of Cancer, Humans, Ki-67 Antigen genetics, Ki-67 Antigen metabolism, Melanoma-Specific Antigens genetics, Melanoma-Specific Antigens metabolism, Observer Variation, gp100 Melanoma Antigen, Immunohistochemistry methods, In Situ Hybridization, Fluorescence methods, Melanoma diagnosis, Nevus, Pigmented diagnosis, Skin Neoplasms diagnosis
- Abstract
The treatment of melanoma requires early diagnosis and extensive surgical removal of the primary tumor. The differential diagnosis between a melanoma and a nevus is sometimes difficult from a histopathologic point of view and could require ancillary diagnostic tools. Recently, both fluorescent in situ hybridization (FISH) and p16-Ki67-HMB45 combined immunohistochemistry have been proposed as examples of ancillary diagnostic methods to help classify melanocytic tumors as benign or malignant. In this study, we compare FISH and p16-Ki-67-HMB45 immunohistochemistry in a set of melanomas and nevi. A total of 101 formalin-fixed and paraffin-embedded tumor samples (44 melanomas and 57 nevi) were analyzed using FISH for chromosomes 6, 8, 9, and 11 and p16-Ki-67-HMB45 immunohistochemistry. Any chromosomal imbalances and/or a p16-Ki-67-HMB45 immunohistochemistry combined score of 4 or higher were considered to reflect a "favor" malignant tumor. Using FISH, 42 out of 44 melanomas presented at least 1 chromosomal imbalance, whereas 2 melanomas and all nevi did not. Each melanoma, including 6 challenging tumors, had a p16-Ki-67-HMB45 immunohistochemistry combined score of 4 or higher and every nevus had a score inferior to 4. This reflects an excellent strength of agreement between FISH, immunohistochemistry, and definitive histopathologic diagnosis in our tumor set. We conclude that both FISH and p16-Ki67-HMB45 combined immunohistochemistry are valuable ancillary diagnostic tools to help pathologists classify melanocytic tumors as nevi or melanomas.
- Published
- 2018
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26. Asbestos-related lung cancers are rarely associated with ALK , ROS1 and RET rearrangements.
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Uguen M, Dewitte JD, Loddé B, Marcorelles P, and Uguen A
- Subjects
- Asbestos, Carcinoma, Non-Small-Cell Lung, Humans, Mutation, Occupational Exposure, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-ret genetics, Lung Neoplasms, Smokers
- Abstract
Competing Interests: Conflict of interest: None declared.
- Published
- 2018
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27. Do pregnancies reduce iron overload in HFE hemochromatosis women? results from an observational prospective study.
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Scotet V, Saliou P, Uguen M, L'Hostis C, Merour MC, Triponey C, Chanu B, Nousbaum JB, Le Gac G, and Ferec C
- Subjects
- Adult, Alcohol Drinking epidemiology, Alcohol Drinking physiopathology, Body Mass Index, Female, Ferritins blood, France epidemiology, Hemochromatosis Protein genetics, Homozygote, Humans, Iron Overload diagnosis, Iron Overload etiology, Male, Menopause blood, Middle Aged, Pregnancy, Regression Analysis, Risk Factors, Sex Factors, Hemochromatosis diagnosis, Hemochromatosis genetics, Hemochromatosis physiopathology, Hemochromatosis therapy, Iron blood, Phlebotomy methods, Phlebotomy statistics & numerical data, Pregnancy Complications, Hematologic diagnosis, Pregnancy Complications, Hematologic genetics, Pregnancy Complications, Hematologic physiopathology, Pregnancy Complications, Hematologic therapy
- Abstract
Background: HFE hemochromatosis is an inborn error of iron metabolism linked to a defect in the regulation of hepcidin synthesis. This autosomal recessive disease typically manifests later in women than men. Although it is commonly stated that pregnancy is, with menses, one of the factors that offsets iron accumulation in women, no epidemiological study has yet supported this hypothesis. The aim of our study was to evaluate the influence of pregnancy on expression of the predominant HFE p.[Cys282Tyr];[Cys282Tyr] genotype., Methods: One hundred and forty p.Cys282Tyr homozygous women enrolled in a phlebotomy program between 2004 and 2011 at a blood centre in western Brittany (France) were included in the study. After checking whether the disease expression was delayed in women than in men in our study, the association between pregnancy and iron overload was assessed using multivariable regression analysis., Results: Our study confirms that women with HFE hemochromatosis were diagnosed later than men cared for during the same period (52.6 vs. 47.4 y., P < 0.001). Compared to no pregnancy, having at least one pregnancy was not associated with lower iron markers. In contrast, the amount of iron removed by phlebotomies appeared significantly higher in women who had at least one pregnancy (e
β = 1.50, P = 0.047). This relationship disappeared after adjustment for confounding factors (eβ = 1.35, P = 0.088)., Conclusions: Our study shows that pregnancy status has no impact on iron markers level, and is not in favour of pregnancy being a protective factor in progressive iron accumulation. Our results are consistent with recent experimental data suggesting that the difference in disease expression observed between men and women may be explained by other factors such as hormones.- Published
- 2018
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28. Medical laboratory technician professional pathologies: a 2006-2016 literature review.
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Pougnet R, Loddé B, Uguen M, Sawicki B, and Pougnet L
- Subjects
- Humans, Musculoskeletal Diseases epidemiology, Neck Pain epidemiology, Prevalence, Risk Factors, Medical Laboratory Personnel statistics & numerical data, Occupational Diseases epidemiology
- Abstract
The trade of laboratory technician (TL) exposes to many risks to health, because of biological or chemical or physical exposures. But the TL occupation is constantly evolving, the techniques are constantly changing. The purpose of this article is to take stock of the occupational TL pathologies which were recently described in the literature. This is a literature review, based on Medline® and Scopus® medical databases, on publications between 01/01/2006 and 31/12/2016. The research was conducted in French and English. Only articles about TL in Hospital or Teaching Hospital were selected. Twenty-eight articles were studied. The main infectious pathology described was brucellosis and a case of meningitis was studied. The cutaneous allergies reported concerned sensitization to certain solvents. There was no allergy to latex. Musculoskeletal disorders (MSD) were studied in 4 articles. The main MSDs were low back pain and neck pain. Several articles have alerted on the occurrence of burnout syndrome (BO). However, no prevalence studies were conducted over the period studied. In conclusion, TL can present many occupational pathologies. Few articles studied the prevalence of MSD and BO.
- Published
- 2017
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29. Another Point of View About Cyclin D1 and p16 Expression in Blue Nevi and Malignant Melanomas.
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Uguen A, Guibourg B, and Uguen M
- Subjects
- Cyclin D1 metabolism, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Humans, Immunohistochemistry, Staining and Labeling, Cyclin D1 genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, Gene Expression Regulation, Neoplastic, Melanoma physiopathology, Nevus, Blue physiopathology
- Published
- 2017
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30. Asbestos-related lung cancers: A retrospective clinical and pathological study.
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Uguen M, Dewitte JD, Marcorelles P, Loddé B, Pougnet R, Saliou P, De Braekeleer M, and Uguen A
- Abstract
Exposure to asbestos results in serious risks of developing mesothelioma and lung cancer. The link between asbestos exposure and lung carcinoma is well established. Nevertheless, precise histopathological data are poorly considered when investigating the asbestos-cancer link in a compensatory approach. In the present study, we aim to describe the features of individuals with compensated lung cancer who were referred to an occupational disease center, regarding occupational exposure to asbestos, smoking history and pathological data. We led a retrospective study of compensated ARLC cases seen in our occupational disease center between 2003 and 2013. A total of 146 men were included (mean age at diagnosis, 63.2 years) of whom approximately 90% were heavy current or former smokers (mean value, 30.4 packs/year). The major industries associated with the lung cancer cases were shipbuilding (69.9%), and building construction (7.5%) in this harbor region. The results of the present study showed that lung upper lobe was most prevalent (61.6%) and an excess of adenocarcinoma was found (45.9%), followed by squamous cell carcinoma (38.4%) as well as thoracic sarcomas (2.1%). Neoplasm was not histologically proven in 6.8% of the cases. Subsequent pathology examinations also reclassified 2 tumors as metastases from esophageal and laryngeal origins. In conclusion, smoking prevention should be encouraged in asbestos-exposed workers as reflected by the number of smokers with asbestos-related lung cancer. Thus, histological data should be considered further to evaluate the potent relationship between asbestos exposure and lung malignancy, especially in a compensatory approach.
- Published
- 2017
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31. Detection of Mismatch Repair Deficiency in Colorectal Cancers: Is It Really Time to Eliminate Immunohistochemistry?
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Le Flahec G, Uguen M, and Uguen A
- Subjects
- Brain Neoplasms, High-Throughput Nucleotide Sequencing, Humans, Immunohistochemistry, Colorectal Neoplasms, Neoplastic Syndromes, Hereditary
- Published
- 2017
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32. BRAF Mutational Intertumoral Discrepancies: Think About Technical Limitations Instead of Mutational Heterogeneity.
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Uguen A and Uguen M
- Published
- 2017
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33. VE1 Immunohistochemistry Fails to Detect Most of the Non-BRAFV600E Mutations in Melanoma.
- Author
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Uguen A and Uguen M
- Subjects
- Amino Acid Substitution, Antibodies, Monoclonal metabolism, Antibody Specificity, Biomarkers, Tumor genetics, Cross Reactions, Diagnostic Errors, False Negative Reactions, Gene Expression, Humans, Immunohistochemistry standards, Melanoma genetics, Melanoma pathology, Point Mutation, Protein Binding, Proto-Oncogene Proteins B-raf genetics, Skin Neoplasms genetics, Skin Neoplasms pathology, Antibodies, Monoclonal chemistry, Biomarkers, Tumor chemistry, Melanoma diagnosis, Proto-Oncogene Proteins B-raf chemistry, Skin Neoplasms diagnosis
- Published
- 2016
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34. Fluorescence in situ hybridization testing of chromosomes 6, 8, 9 and 11 in melanocytic tumors is difficult to automate and reveals tumor heterogeneity in melanomas.
- Author
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Uguen A, Uguen M, Talagas M, Gobin E, Marcorelles P, and De Braekeleer M
- Abstract
Malignant melanomas may be difficult to differentiate from benign nevi on the basis of histology. Contrary to nevi, the majority of melanomas harbor chromosomal imbalances. Comparative genomic hybridization-based and fluorescence in situ hybridization (FISH) tests can help differentiating malignant from benign tumors. In the present study, eight-bacterial artificial chromosome (BAC) probes targeting chromosomes 6, 8, 9 and 11 were tested by FISH, and compared with a commercial four-color FISH probe set targeting chromosomes 6 and 11 in a first set of 62 tissue microarray-included melanocytic tumors (47 melanomas and 15 nevi). A second set of 108 tumors (70 melanomas and 38 nevi) was analyzed with the eight-probes kit, and manual counting was compared with the newly developed automated FISH signals counting and with semi-quantitative visual detection of chromosomal imbalances. Intra-tumor heterogeneity was also evaluated in 12 melanomas and 10 patients with paired melanoma samples. Testing the tumors from the first set with the commercial kit and the eight-probes test permitted to correctly identify 45/47 and 47/47 melanomas, respectively. In the second tumor set, 65/70 malignant tumors presented at least one chromosomal imbalance, whereas none was detected in the nevi. The agreement between manual and automated signals counting was better in good-quality FISH slides compared with poor-quality slides. Semi-quantitative visual appreciation of chromosomal imbalances also reached strong agreement with exact manual counting. In addition, a frequent cytogenetic heterogeneity within melanomas and between paired tumors was noticed in patients with metastatic melanomas. To conclude, FISH testing targeting chromosomes 6, 8, 9 and 11 enabled to differentiate the majority of melanomas from nevi but was difficult to automate. Tumor cytogenetic heterogeneity was frequent and could impair FISH testing.
- Published
- 2016
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35. ALK Expression in Melanomas: Looking for a Needle in a Haystack.
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Uguen A, Uguen M, and Guibourg B
- Subjects
- Anaplastic Lymphoma Kinase, Humans, Melanoma, Receptor Protein-Tyrosine Kinases metabolism
- Published
- 2016
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36. Influence of risk assessment inspection on the prevention of nosocomial infection.
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Uguen M, Daniel L, Cosse M, Cabon S, Canevet M, Le Grand A, Baron R, and Saliou P
- Subjects
- Humans, Risk Assessment, Cross Infection epidemiology, Cross Infection prevention & control, Infection Control methods, Infection Control organization & administration
- Published
- 2016
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37. Investigation of Legionella pneumophila Outbreak: Effectiveness of Clinical and Genomic Methods.
- Author
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Saliou P, Fangous MS, Uguen M, Le Bars H, Narbonne V, Payan C, Tandé D, Baron R, and Héry-Arnaud G
- Subjects
- Disease Outbreaks, Genomics, Humans, Legionella, Legionella pneumophila genetics, Legionnaires' Disease epidemiology
- Published
- 2016
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38. About BRAF Mutations and p16 Expression in Melanomas Associated With Blue Nevi or Mimicking Cellular Blue Nevi.
- Author
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Uguen A and Uguen M
- Subjects
- Humans, Mutation, Nevus, Epithelioid and Spindle Cell, Proto-Oncogene Proteins B-raf genetics, Skin Neoplasms, Melanoma, Nevus, Blue
- Published
- 2016
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39. Fungal Outbreaks and Infection Prevention During Demolition: Influence of High-Efficiency Particulate Air Filtration.
- Author
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Saliou P, Uguen M, Le Bars H, Le Clech L, and Baron R
- Subjects
- Humans, Cross Infection prevention & control, Disease Outbreaks prevention & control, Hospital Design and Construction, Mycoses prevention & control
- Published
- 2016
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40. Dysbaric osteonecrosis in professional divers: two case reports.
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Uguen M, Pougnet R, Uguen A, Cornec D, Quintin-Roué I, Dewitte JD, and Loddé B
- Subjects
- Adult, Femur Head Necrosis diagnosis, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Occupational Diseases diagnosis, Osteonecrosis diagnosis, Retrospective Studies, Compressed Air adverse effects, Diving adverse effects, Femur Head Necrosis therapy, Humeral Head, Occupational Diseases therapy, Osteonecrosis therapy
- Abstract
Aim: Dysbaric osteonecrosis (DON) is an avascular bone necrosis seen in divers and compressed-air workers. It continues to be a significant occupational hazard that has important medical and social consequences for professional divers. The prevalence of DON varied between 0% and 70.6% in professional divers in the literature. This paper seeks to describe the distribution of the lesions, the diagnosis and the prognosis of individuals affected by DON referred to a French occupational disease center., Method: We led a retrospective study by searching for cases of DON in the medical files of divers seen in our occupational disease center between 2001 and 2014. 332 professional divers consulted in our center between 2001 and 2014.Clinical, radiological and pathological data were collected to report about the cases., Results: We report two cases of DON in divers. The first case is a left femoral head lesion in a 38-year-old man who underwent a total hip arthroplasty. Histopathological examination of the native femoral head confirmed the diagnosis of DON. The second case of DON concerns the humeral heads in a 52-year-old man. The treatment was conservative in this second case. In both cases the patients have been declared definitely medically unfit to dive and were financially compensated. Conclusion: The prognosis of DON raises the question of the ability among employees whose rehabilitation is difficult.
- Published
- 2015
41. Predicted nine-year risk of diabetes among professional divers: a prospective study.
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Pougnet R, Uguen M, Verdier G, Pougnet L, Lucas D, Loddé B, and Dewitte JD
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- Adult, Diabetes Mellitus epidemiology, Diving statistics & numerical data, Female, France epidemiology, Humans, Male, Memory, Episodic, Risk Factors, Diabetes Mellitus etiology, Diving adverse effects
- Abstract
Background: The purpose of this study was to assess diabetes predictive score for professional divers followed-up in one medical centre in France., Materials and Methods: This prospective study, performed during 2013, included professional divers who were followed in a French maritime medicine centre. Data about their professional history of diving and dive profiles were collected. The clinical and biological data collected included: age, waist circumference, biometrics, body mass index, smoking status, blood pressure, practicing sports, glycaemia, triglyceridaemia, total cholesterolaemia, HDL and LDL cholesterolaemia. The predicted 9-year risk of diabetes was calculated according to the DESIRE score. Data were analysed using Epidata® software, by Pearson c2 test or by Fisher's exact test, by analysis of variance or Kruskal-Wallis test, and by Spearman correlation coefficient., Results: Out of the 64 deep-sea divers taking part in the study, diabetes risk was estimated for 60 divers. The predictive 9-year risk of diabetes was higher than 10% for 31.7% of the divers and higher than 30% for 6.7% of the divers., Conclusions: In France, people with diabetes have been declared definitely medically unfit to dive. The interest to assess the prevalence of risk factors and the predictive risk of diabetes arises from the need for prevention.
- Published
- 2015
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42. Dysbaric osteonecrosis among professional divers: a literature review.
- Author
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Uguen M, Pougnet R, Uguen A, Loddé B, and Dewitte JD
- Subjects
- Cross-Sectional Studies, Femur, Humans, Humerus, Observational Studies as Topic, Occupational Diseases diagnosis, Occupational Diseases epidemiology, Occupational Diseases therapy, Osteonecrosis diagnosis, Osteonecrosis epidemiology, Osteonecrosis therapy, Prognosis, Risk Factors, Diving adverse effects, Occupational Diseases etiology, Osteonecrosis etiology
- Abstract
Aim: Dysbaric osteonecrosis (DON) continues to be a significant occupational hazard that has significant medical and social consequences for professional divers. This review aims to evaluate the prevalence and risk factors of DON among professional divers and to summarize the scientific knowledge regarding distribution of the lesions as well as disease prognosis and treatment., Method: A literature review using the Medline database., Results: The prevalence of DON varies between 0 and 70.6% in professional divers, and its prevalence is highest in Turkey, Hawaii, Korea and Japan but is dependent on activity and medical monitoring. The risk of DON is very low for military divers who strictly obey the decompression rules and who undergo periodic medical examination. DON pre- dominately occurs in the proximal part of the femur and humerus. In a majority of cases, DON will progress despite the absence of further dysbaric exposure., Conclusion: The pathophysiology of the disease is incompletely understood and other etiological factors are perhaps being overlooked.
- Published
- 2014
43. Longitudinal change in professional divers' lung function: literature review.
- Author
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Pougnet R, Pougnet L, Lucas D, Uguen M, Henckes A, Dewitte JD, and Loddé B
- Subjects
- Forced Expiratory Flow Rates, Forced Expiratory Volume, Humans, Vital Capacity, Diving physiology, Lung physiopathology, Occupational Health
- Abstract
Background: The aim of this study was to assess changes in lung function of professional divers., Materials and Methods: This is a review of the literature. Only studies about professional divers were included. All published studies between 01.01.1984 and 07.01.2014 were systematically searched. The search was performed in Medline and Embase databases and in the "Medicina Maritima" journal. The results of pulmonary function tests were extracted from each study., Results: Fifteen articles were found. Four studies showed a significant decrease in forced vital capacity (FVC). Five studies demonstrated a significant decrease in forced expiratory flows (FEF) at 75% and 50% of FVC expired (FEF75% and FEF50%) after 3 years of diving. Seven studies demonstrated a significant decrease in forced expiratory volume in 1 second (FEV1) after 3 years of diving. But only 2 studies did an age-standardisation so that only 1 study demonstrated a significant decrease in FEV1 after age-standardisation. Three articles showed a decrease in transfer factor for carbon monoxide (TLCO) after 5 years. Dives parameters (like depth, number by year) were not always related to variations on the different lung variables., Conclusions: This literature review showed a decrease in TLCO, FEF75% and FEF25-75%. One wonders whether these variations are due to the age or to diving. The results of such a long-term study would be interesting and might help to guide fundamental research.
- Published
- 2014
- Full Text
- View/download PDF
44. Preclinical evaluation of the abuse potential of Pitolisant, a histamine H₃ receptor inverse agonist/antagonist compared with Modafinil.
- Author
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Uguen M, Perrin D, Belliard S, Ligneau X, Beardsley PM, Lecomte JM, and Schwartz JC
- Subjects
- Animals, Behavior, Addictive prevention & control, Behavior, Animal drug effects, Benzhydryl Compounds adverse effects, Central Nervous System Stimulants adverse effects, Dopamine chemistry, Dopamine metabolism, Dopaminergic Neurons drug effects, Dopaminergic Neurons metabolism, Dose-Response Relationship, Drug, Drug Antagonism, Drug Evaluation, Preclinical, Drug Inverse Agonism, Drugs, Investigational administration & dosage, Drugs, Investigational therapeutic use, Histamine Agonists administration & dosage, Histamine Agonists therapeutic use, Histamine Antagonists administration & dosage, Histamine Antagonists therapeutic use, Macaca mulatta, Male, Mice, Modafinil, Motor Activity drug effects, Nucleus Accumbens drug effects, Nucleus Accumbens metabolism, Piperidines administration & dosage, Piperidines therapeutic use, Rats, Receptors, Histamine H3 chemistry, Wakefulness-Promoting Agents administration & dosage, Wakefulness-Promoting Agents therapeutic use, Behavior, Addictive chemically induced, Drugs, Investigational adverse effects, Histamine Agonists adverse effects, Histamine Antagonists adverse effects, Piperidines adverse effects, Receptors, Histamine H3 metabolism, Wakefulness-Promoting Agents adverse effects
- Abstract
Background and Purpose: Pitolisant, a histamine H₃ receptor inverse agonist/antagonist is currently under Phase III clinical trials for treatment of excessive daytime sleepiness namely in narcoleptic patients. Its drug abuse potential was investigated using in vivo models in rodents and monkeys and compared with those of Modafinil, a psychostimulant currently used in the same indications., Experimental Approach: Effects of Pitolisant on dopamine release in the nucleus accumbens, on spontaneous and cocaine-induced locomotion, locomotor sensitization were monitored. It was also tested in three standard drug abuse tests i.e. conditioned place preference in rats, self-administration in monkeys and cocaine discrimination in mice as well as in a physical dependence model., Key Results: Pitolisant did not elicit any significant changes in dopaminergic indices in rat nucleus accumbens whereas Modafinil increased dopamine release. In rodents, Pitolisant was without any effect on locomotion and reduced the cocaine-induced hyperlocomotion. In addition, no locomotor sensitization and no conditioned hyperlocomotion were evidenced with this compound in rats whereas significant effects were elicited by Modafinil. Finally, Pitolisant was devoid of any significant effects in the three standard drug abuse tests (including self-administration in monkeys) and in the physical dependence model., Conclusions and Implications: No potential drug abuse liability for Pitolisant was evidenced in various in vivo rodent and primate models, whereas the same does not seem so clear in the case of Modafinil., (© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.)
- Published
- 2013
- Full Text
- View/download PDF
45. Brain histamine and schizophrenia: potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649.
- Author
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Ligneau X, Landais L, Perrin D, Piriou J, Uguen M, Denis E, Robert P, Parmentier R, Anaclet C, Lin JS, Burban A, Arrang JM, and Schwartz JC
- Subjects
- Administration, Oral, Animals, Disease Models, Animal, Mice, Receptors, Histamine H3 physiology, Histamine Antagonists therapeutic use, Piperidines therapeutic use, Receptors, Histamine H3 metabolism, Schizophrenia drug therapy
- Abstract
BF2.649, a high affinity and selective non-imidazole histamine H(3)-receptor antagonist/inverse agonist, was found to easily enter the brain after oral administration to mice: it displayed a ratio of brain/plasma levels of about 25 when considering either C(max) or AUC values. At low oral doses (2.5-20mg/kg), it elicited in mice a dose-dependent wakening effect accompanied with a shift towards high frequency waves of the EEG, a sign of cortical activation. DOPAC/dopamine ratios were enhanced in the prefrontal cortex but not in the striatum, indicating a selective activation of a sub-population of dopaminergic neurons. BF2.649 showed significant inhibitory activity in several mouse models of schizophrenia. It reduced locomotor hyperactivity elicited by methamphetamine or dizolcipine without significantly affecting spontaneous locomotor activity when administered alone. It also abolished the apomorphine-induced deficit in prepulse inhibition. These observations suggest that H(3)-receptor inverse agonists/antagonists deserve attention as a novel class of antipsychotic drugs endowed with pro-cognitive properties.
- Published
- 2007
- Full Text
- View/download PDF
46. Phage display as a tool for the directed evolution of enzymes.
- Author
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Fernandez-Gacio A, Uguen M, and Fastrez J
- Subjects
- Allosteric Site, Bacteriophages genetics, Catalytic Domain genetics, Chromatography, Affinity methods, Enzyme Stability, Enzymes metabolism, Models, Biological, Protein Engineering methods, Substrate Specificity, Directed Molecular Evolution methods, Enzymes genetics, Peptide Library
- Abstract
Since its introduction in 1985, phage display has had a tremendous impact on the discovery of peptides that bind to a variety of receptors, the generation of binding sites within predefined scaffolds, and the creation of high-affinity antibodies without immunization. Its application to enzymology has required the development of techniques that couple enzymatic activity to selection protocols based on affinity chromatography. Here, we describe both indirect methods, using transition-state analogues and suicide substrates, and direct methods, using the ability of active phage-enzymes to transform substrate into product. The methods have been applied to large libraries for mechanistic-based studies and to generate variants with new or improved properties. In addition, such techniques have been successfully used to select catalytic antibodies and improve their catalytic efficiency.
- Published
- 2003
- Full Text
- View/download PDF
47. The Enterococcus faecalis gene encoding the novel general stress protein Gsp62.
- Author
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Rincé A, Uguen M, Le Breton Y, Giard JC, Flahaut S, Dufour A, and Auffray Y
- Subjects
- Amino Acid Sequence, Bacterial Proteins chemistry, Bacterial Proteins isolation & purification, Bacterial Proteins metabolism, Base Sequence, Enterococcus faecalis metabolism, Gene Deletion, Gene Expression Regulation, Bacterial, Heat-Shock Proteins chemistry, Heat-Shock Proteins isolation & purification, Heat-Shock Proteins metabolism, Molecular Sequence Data, Promoter Regions, Genetic, Sequence Analysis, DNA, Transcription, Genetic, beta-Galactosidase metabolism, Bacterial Proteins genetics, Enterococcus faecalis genetics, Enterococcus faecalis physiology, Heat-Shock Proteins genetics
- Abstract
The Enterococcus faecalis general stress protein Gsp62 was purified using two-dimensional gel electrophoresis and its 25 N-terminal amino acid sequence determined. Analysis of the corresponding gene revealed that the gsp62 product is a 172 aa protein. Transcriptional analysis of gsp62 gave evidence for a monocistronic mRNA, the synthesis of which was induced at the onset of stationary phase and in response to heat shock, acid pH, detergents (i.e. SDS or bile salts), ethanol, tert-butyl hydroperoxide, sodium chloride and, to a lesser extent, hydrogen peroxide. 5' rapid amplification of cDNA ends by PCR experiments showed that gsp62 transcription initiates 30 nt upstream of the ATG start codon. Although gsp62 expression was induced in response to various stresses, its disruption had no significant effect on the cell survival after each individual stress. Two-dimensional protein gels from wild-type and mutant cells revealed no pleiotropic effect of the mutation on protein synthesis. Transcriptional fusions with the lacL lacM beta-galactosidase genes showed that an inverted repeat located upstream of the promoter is required for transcriptional induction by environmental stresses but not by entrance into stationary phase. Two distinct mechanisms responding to different signals are thus involved in gsp62 induction.
- Published
- 2002
- Full Text
- View/download PDF
48. The LcnC homologue cannot replace LctT in lacticin 481 export.
- Author
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Uguen M and Uguen P
- Subjects
- ATP-Binding Cassette Transporters metabolism, Biological Transport, Lactococcus lactis genetics, Plasmids genetics, Recombination, Genetic, ATP-Binding Cassette Transporters genetics, Bacterial Proteins genetics, Bacterial Proteins metabolism, Bacteriocins, Lactococcus lactis metabolism
- Abstract
Lacticin 481 is produced by Lactococcus lactis subsp. lactis and belongs to subgroup AII of the lanthionine-containing bacteriocins. The putative homodimeric LctT involved in lacticin 481 production shares significant similarities with the 'LcnC' protein encoded by 'lcnC', located on the chromosome of the lactic acid bacterium, L. lactis IL1403. LctT and 'LcnC' belong to the recently defined family of AMS (ABC transporter maturation and secretion) proteins. Inactivation of the 'lcnC' gene demonstrates that it is not responsible for the weak lacticin 481 production observed in a strain expressing only the precursor peptide LctA, and the modification enzyme LctM. This result indicates that the two AMS proteins, 'LcnC' and LctT, are not interchangeable in the machinery of processing/export of lacticin 481.
- Published
- 2002
- Full Text
- View/download PDF
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