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JOURNAL ARTICLE
Jérémy Brunet, Zaineb Choucha, Marion Gransagne, Houda Tabbal, Min-Wen Ku, Julian Buchrieser, Priyanka Fernandes, Damien Batalie, Jodie Lopez, Laurence Ma, Evelyne Dufour, Emeline Simon, David Hardy, Stéphane Petres, Françoise Guinet, Helene Strick-Marchand, Marc Monot, Pierre Charneau, Laleh Majlessi, W Paul Duprex, Christiane Gerke, Annette Martin, Nicolas Escriou
In the early COVID-19 pandemic with urgent need for countermeasures, we aimed at developing a replicating viral vaccine using the highly efficacious measles vaccine as vector, a promising technology with prior clinical proof of concept. Building on our successful pre-clinical development of a measles virus (MV)-based vaccine candidate against the related SARS-CoV, we evaluated several recombinant MV expressing codon-optimized SARS-CoV-2 spike glycoprotein. Candidate V591 expressing a prefusion-stabilized spike through introduction of two proline residues in HR1 hinge loop, together with deleted S1/S2 furin cleavage site and additional inactivation of the endoplasmic reticulum retrieval signal, was the most potent in eliciting neutralizing antibodies in mice...
April 2, 2024: Journal of Virology
#2
JOURNAL ARTICLE
Javier Fernández, Miquel Lozano, Mireia Torres, Raquel Horrillo, Natalia Afonso, Laura Núñez, Anna Mestre, Alba Pérez, Joan Cid, Montserrat Costa, Vicente Arroyo, Antonio Páez
BACKGROUND & AIMS: Effective treatments for acute-on-chronic liver failure (ACLF) are a major unmet need. This proof-of-concept pilot study was aimed at evaluating the effects of plasma exchange (PE) with albumin 5% (PE-A5%) on albumin functional capacity and organ dysfunction in patients with ACLF. METHODS: Ten adult patients were enrolled in a single-center phase II, prospective, open-label, non-controlled study. Six PE-A5% sessions were performed in 10 days followed by a 1-month follow-up visit...
April 2024: JHEP reports: innovation in hepatology
#3
JOURNAL ARTICLE
Michel Alexander Steiner, Luca Botticelli, Giorgio Bergamini, Emanuela Micioni Di Bonaventura, John Gatfield, Jodi T Williams, Alexander Treiber, Catherine Vaillant, Carlo Cifani, Maria Vittoria Micioni Di Bonaventura
OBJECTIVE: Test the efficacy of the selective orexin 1 receptor (OX1R) antagonist (SO1RA) nivasorexant in an animal model of binge-eating disorder (BED) and study its dose-response relationship considering free brain concentrations and calculated OX1R occupancy. Compare nivasorexant's profile to that of other, structurally diverse SO1RAs. Gain understanding of potential changes in orexin-A (OXA) neuropeptide and deltaFosB (ΔFosB) protein expression possibly underlying the development of the binge-eating phenotype in the rat model used...
March 8, 2024: International Journal of Eating Disorders
#4
JOURNAL ARTICLE
Nina Possemis, Frans Verhey, Jos Prickaerts, Arjan Blokland, Inez Ramakers
BACKGROUND: Research into the neurobiological underpinnings of learning and memory has demonstrated the cognitive-enhancing effects associated with diverse classes of phosphodiesterase (PDE) inhibitors. Specific PDE inhibitors have been identified to improve neuronal communication through selective inhibition of PDE activity. Roflumilast, a PDE4 inhibitor, has demonstrated efficacy in enhancing episodic memory in healthy adults and elderly participants with pronounced memory impairment, indicative of amnestic mild cognitive impairment (aMCI)...
March 4, 2024: Trials
#5
JOURNAL ARTICLE
Jodi T Williams, Martin H Bolli, Christine Brotschi, Thierry Sifferlen, Michel A Steiner, Alexander Treiber, John Gatfield, Christoph Boss
The orexin system consists of two neuropeptides (orexins A and B) and two receptors (OX1 and OX2). Selective OX1 receptor antagonists (SO1RA) are gaining interest for their potential use in the treatment of CNS disorders, including substance abuse, eating, obsessive compulsive, or anxiety disorders. While blocking OX2 reduces wakefulness, the expected advantage of selectively antagonizing OX1 is the ability to achieve clinical efficacy without the promotion of sleep. Herein we report our discovery efforts starting from a dual orexin receptor antagonist and describe a serendipitous finding that triggered a medicinal chemistry program that culminated in the identification of the potent SO1RA ACT-539313...
February 8, 2024: Journal of Medicinal Chemistry
#6
RANDOMIZED CONTROLLED TRIAL
Renata Siciliani Scalco, Jasper M Morrow, Andreea Manole, Iwona Skorupinska, Federico Ricciardi, Emma Matthews, Michael G Hanna, Doreen Fialho
The aim of this study was to establish whether bumetanide can abort an acute attack of weakness in patients with HypoPP. This was a randomised, double-blind, cross-over, placebo-controlled phase II clinical trial. Focal attack of weakness was induced by isometric exercise of ADM followed by rest (McManis protocol). Participants had two study visits and received either placebo or 2 mg bumetanide at attack onset (defined as 40 % decrement in the abductor digiti minimi CMAP amplitude from peak). CMAP measurements assessed attack severity and duration...
February 2024: Neuromuscular Disorders: NMD
#7
JOURNAL ARTICLE
Wen Zhang, Glen Laird, Josh Chen, Ying Yuan
Existing phase II clinical trial designs focus on a single scalar endpoint, such as a binary, continuous, or survival endpoint. In some clinical trials, such as pain management studies, the efficacy endpoint of interest is measured longitudinally. We propose a Bayesian phase II design for such clinical trials. We model the longitudinal measurement process using Bayesian hierarchical model, where subject-specific trajectory shrinks toward the population trajectory to borrow information across subjects. The Bayesian penalized spline is used to model subject-specific and population trajectories without making strong parametric assumption on their shapes...
November 8, 2023: Statistics in Medicine
#8
JOURNAL ARTICLE
Fulvio Di Stefano, Christelle Rodrigues, Stephanie Galtier, Sandrine Guilleminot, Veronique Robert, Mauro Gasparini, Gaelle Saint-Hilary
Receptor occupancy in targeted tissues measures the proportion of receptors occupied by a drug at equilibrium and is sometimes used as a surrogate of drug efficacy to inform dose selection in clinical trials. We propose to incorporate data on receptor occupancy from a phase I study in healthy volunteers into a phase II proof-of-concept study in patients, with the objective of using all the available evidence to make informed decisions. A minimal physiologically based pharmacokinetic modeling is used to model receptor occupancy in healthy volunteers and to predict it in the patients of a phase II proof-of-concept study, taking into account the variability of the population parameters and the specific differences arising from the pathological condition compared to healthy volunteers...
December 2023: Biometrical Journal. Biometrische Zeitschrift
#9
JOURNAL ARTICLE
Herve Ghesquieres, Fanny Cherblanc, Aurelien Belot, Sophie Micon, Krimo Bouabdallah, Cyril Esnault, Luc-Matthieu Fornecker, Katia Thokagevistk, Maxime Bonjour, Fontanet Bijou, Corinne Haioun, Nadine Morineau, Loïc Ysebaert, Gandhi Damaj, Benoit Tessoulin, Stéphanie Guidez, Franck Morschhauser, Catherine Thieblemont, Adrien Chauchet, Remy Gressin, Fabrice Jardin, Christophe Fruchart, Gaelle Labouré, Ludovic Fouillet, Pauline Lionne-Huyghe, Antoine Bonnet, Laure Lebras, Sandy Amorim, Cecile Leyronnas, Gaelle Olivier, Romain Guieze, Roch Houot, Vincent Launay, Bernard Drénou, Olivier Fitoussi, Laurence Detourmignies, Julie Abraham, Carole Soussain, Florence Lachenal, Gian Matteo Pica, Patrick Fogarty, Pascale Cony-Makhoul, Adeline Bernier, Sandra Le Guyader-Peyrou, Alain Monnereau, Frédéric Boissard, Cédric Rossi, Vincent Camus
Real-world data are essential to complement clinical trial (CT) data, but major challenges remain, like data quality. REal world dAta in LYmphoma and Survival in Adults (REALYSA) is a prospective non-interventional multicentric cohort started in 2018 (NCT03869619) including patients newly diagnosed with lymphoma in France. Herein is a proof-of-concept analysis on first-line DLBCL patients to (i) evaluate the capacity of the cohort to provide robust data through a multi-step validation process; (ii) assess the consistency of the results; (iii) conduct an exploratory transportability assessment of two recent phase 3 CT (POLARIX, SENIOR)...
October 24, 2023: Blood Advances
#10
JOURNAL ARTICLE
Adam M Thomas, Marta Serafini, Emma K Grant, Edward A J Coombs, Joseph P Bluck, Matthias Schiedel, Michael A McDonough, Jessica K Reynolds, Bernadette Lee, Michael Platt, Vassilena Sharlandjieva, Philip C Biggin, Fernanda Duarte, Thomas A Milne, Jacob T Bush, Stuart J Conway
Target validation remains a challenge in drug discovery, which leads to a high attrition rate in the drug discovery process, particularly in Phase II clinical trials. Consequently, new approaches to enhance target validation are valuable tools to improve the drug discovery process. Here, we report the combination of site-directed mutagenesis and electrophilic fragments to enable the rapid identification of small molecules that selectively inhibit the mutant protein. Using the bromodomain-containing protein BRD4 as an example, we employed a structure-based approach to identify the L94C mutation in the first bromodomain of BRD4 [BRD4(1)] as having a minimal effect on BRD4(1) function...
October 24, 2023: ACS Chemical Biology
#11
JOURNAL ARTICLE
Jennifer Grau-Sánchez, Ancor Serrano, Jesús Villoria, Thiago Carnaval, María F Porto, Lorena Zapata, Montse Flores-García, Emma Segura, Jessica Garrido-Pedrosa, Antoni Rodríguez-Fornells, Víctor Fernández-Dueñas, Sebastian Videla
BACKGROUND: Chronic non-cancer pain (CNCP) treatment's primary goal is to maintain physical and mental functioning while improving quality of life. Opioid use in CNCP patients has increased in recent years, and non-pharmacological interventions such as music listening have been proposed to counter it. Unlike other auditive stimuli, music can activate emotional-regulating and reward-regulating circuits, making it a potential tool to modulate attentional processes and regulate mood. This study's primary objective is to provide the first evidence on the distinct (separate) effects of music listening as a coadjuvant maintenance analgesic treatment in CNCP patients undergoing opioid analgesia...
September 11, 2023: BMJ Open
#12
JOURNAL ARTICLE
Susan L McElroy, Preciosa M Coloma, Benjamin Berger, Anna I Guerdjikova, J Mark Joyce, Michael R Liebowitz, Scott Pain, Cristina Rabasa
OBJECTIVE: This Phase II, placebo-controlled, double-blind study investigated the efficacy, safety, and tolerability of nivasorexant in the treatment of adults with moderate to severe binge-eating disorder (BED). METHODS: Adults meeting the DSM-5 BED criteria were randomized 1:1 to placebo or nivasorexant (100 mg b.i.d.). The primary endpoint was the change from baseline to Week 12 in the number of binge eating (BE) days per week. Exploratory efficacy endpoints included cessation of BE in the last 4 weeks of treatment; and change from baseline to Week 12 in the number of BE episodes/week, the clinician global impression (CGI) of change, the Yale-Brown Obsessive-Compulsive Scale modified for BE, and the Hamilton rating scale for depression (HAMD-17)...
August 16, 2023: International Journal of Eating Disorders
#13
JOURNAL ARTICLE
Heather Coats, Nadia Shive, Bonnie Adrian, Ardith Z Doorenbos, Sarah J Schmiege
BACKGROUND: Care delivery that is not person-centered has been called "discordant care." There has been a shift to incorporate more of a person's narrative into their individual health care treatment plan to reduce discordant care. Aligning with this shift in health care delivery, we developed a person-centered narrative intervention (PCNI) to address existing gaps in delivery of person-centered care. OBJECTIVES: This study aimed to evaluate the feasibility of conducting a randomized study and describe the outcomes of PCNI to usual care on the following person (patient) reported outcomes: perceptions of the quality of communication with their nurses and their psychosocial and existential well-being...
August 3, 2023: Nursing Research
#14
JOURNAL ARTICLE
Angélique Vienot, Marion Jacquin, Magali Rebucci-Peixoto, Dimitri Pureur, François Ghiringhelli, Eric Assenat, Pascal Hammel, Olivier Rosmorduc, Morgane Stouvenot, Manon Allaire, Mohamed Bouattour, Hélène Regnault, Serge Fratte, Eric Raymond, Emilie Soularue, Stéphanie Husson-Wetzel, Vincent Di Martino, Allison Muller, Anne-Laure Clairet, Christine Fagnoni-Legat, Olivier Adotevi, Aurélia Meurisse, Dewi Vernerey, Christophe Borg
BACKGROUND: Several cancer immunotherapies that target the PD-L1/PD-1 pathway show promising clinical activity in patients with hepatocellular carcinoma (HCC). However, the standard of care in first-line treatment with atezolizumab (anti-PD-L1 therapy) in combination with bevacizumab is associated with a limited objective response rate. Telomerase reverse transcriptase (TERT) activation meets the criteria of oncogenic addiction in HCC and could be actionable therapeutic target and a relevant tumor antigen...
July 29, 2023: BMC Cancer
#15
JOURNAL ARTICLE
Miguel Sampayo-Cordero, Bernat Miguel-Huguet, Andrea Malfettone, Elena López-Miranda, María Gion, Elena Abad, Daniel Alcalá-López, Jhudit Pérez-Escuredo, José Manuel Pérez-García, Antonio Llombart-Cussac, Javier Cortés
De-escalation trials in oncology evaluate therapies that aim to improve the quality of life of patients with low-risk cancer by avoiding overtreatment. Non-inferiority randomized trials are commonly used to investigate de-intensified regimens with similar efficacy to that of standard regimens but with fewer adverse effects (ESMO evidence tier A). In cases where it is not feasible to recruit the number of patients needed for a randomized trial, single-arm prospective studies with a hypothesis of non-inferiority can be conducted as an alternative...
2023: Frontiers in Oncology
#16
REVIEW
Christopher C Anderson, Juliana H VanderPluym
Migraine is a common neurological disorder that is present in a large proportion of the global population. It is estimated to occur in around 20.7% of women and 10.7% of men in the United States. The pathophysiology of migraine is a major focus of research, and medications have been developed to interrupt the processes that generate headache and other bothersome symptoms of migraine attacks. The triptan class of medications acts as a direct agonist at the 5-HT1B/D receptor but its use is limited by contraindications for those with coronary or cerebrovascular disease...
2023: Drug Design, Development and Therapy
#17
REVIEW
Helena A Yu, James Chih-Hsin Yang, Hidetoshi Hayashi, Yasushi Goto, Enriqueta Felip, Martin Reck, Michele Vigliotti, Qian Dong, Frédérique Cantero, Pang-Dian Fan, Masayuki Kanai, David W Sternberg, Pasi A Jänne
Limited treatment options exist for EGFR -mutated NSCLC that has progressed after EGFR TKI and platinum-based chemotherapy. HER3 is highly expressed in EGFR -mutated NSCLC, and its expression is associated with poor prognosis in some patients. Patritumab deruxtecan (HER3-DXd) is an investigational, potential first-in-class, HER3-directed antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. In an ongoing phase I study, HER3-DXd demonstrated promising antitumor activity and a tolerable safety profile in patients with EGFR -mutated NSCLC, with or without identified EGFR TKI resistance mechanisms, providing proof of concept of HER3-DXd...
May 22, 2023: Future Oncology
#18
JOURNAL ARTICLE
Jie Zhou, Yan Xu, Yang Chen, Jie Shao, Yaming Su, Zhenhua Xu, Honghui Zhou, Christopher O'Brien
Tesnatilimab is a human immunoglobulin G4 isotype monoclonal antibody that blocks the natural killer group 2 member D (NKG2D) receptor and prevent the downstream signaling of proinflammatory cytokines and cytotoxic mediators. Subcutaneous tesnatilimab was investigated in a phase 2 randomized, double-blind, placebo-controlled trial in patients with moderately to severely active Crohn's disease (CD). While the proof-of-concept Part I of the study demonstrated significant treatment effects, Part II (dose-ranging) revealed unexpected lack of dose-response and a modest degree of clinical benefit for treatment groups...
April 15, 2023: Journal of Clinical Pharmacology
#19
REVIEW
Stefano Cavalieri, Viviana Vitolo, Amelia Barcellini, Sara Ronchi, Angelica Facoetti, Chiara Campo, Catherine Klersy, Silvia Molinelli, Francesco Agustoni, Virginia Valeria Ferretti, Annalisa De Silvestri, Marco Platania, Michele Del Vecchio, Marco Durante, Alexander Helm, Claudia Fournier, Filippo de Braud, Paolo Pedrazzoli, Ester Orlandi, Lisa Licitra
ICONIC is a multicenter, open-label, nonrandomized phase II clinical trial aiming to assess the feasibility and clinical activity of the addition of carbon ion radiotherapy to immune checkpoint inhibitors in cancer patients who have obtained disease stability with pembrolizumab administered as per standard-of-care. The primary end point is objective response rate, and the secondary end points are safety, survival and disease control rate. Translational research is an exploratory aim. The planned sample size is 27 patients...
March 28, 2023: Future Oncology
#20
JOURNAL ARTICLE
Andrew H Ko, Kyu-Pyo Kim, Jens T Siveke, Charles D Lopez, Jill Lacy, Eileen M O'Reilly, Teresa Macarulla, Gulam A Manji, Jeeyun Lee, Jaffer Ajani, Maria Alsina Maqueda, Sun-Young Rha, Janet Lau, Nedal Al-Sakaff, Simon Allen, Danny Lu, Colby S Shemesh, Xinxin Gan, Edward Cha, Do-Youn Oh
BACKGROUND: The MORPHEUS platform comprises multiple open-label, randomized, phase Ib/II trials designed to identify early efficacy and safety signals of treatment combinations across cancers. Atezolizumab (anti-programmed cell death 1 ligand 1 [PD-L1]) was evaluated in combination with PEGylated recombinant human hyaluronidase (PEGPH20). METHODS: In 2 randomized MORPHEUS trials, eligible patients with advanced, previously treated pancreatic ductal adenocarcinoma (PDAC) or gastric cancer (GC) received atezolizumab plus PEGPH20, or control treatment (mFOLFOX6 or gemcitabine plus nab-paclitaxel [MORPHEUS-PDAC]; ramucirumab plus paclitaxel [MORPHEUS-GC])...
March 20, 2023: Oncologist
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