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REVIEW
Yolanda Scoleri-Longo, Petros Pechlivanoglou, Sumit Gupta
Survival rates for pediatric acute lymphoblastic leukemia (pALL) have improved dramatically; relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL) remains challenging. Immunotherapies are rapidly evolving treatments for r/r ALL with limited cost-effectiveness data. This study identifies existing economic evaluations of immunotherapy in pALL and summarizes cost-effectiveness. Medline, Embase, and other databases were searched from inception to October 2022. Cost-effectiveness analyses evaluating immunotherapy in pALL were included...
February 2024: EJHaem
#22
JOURNAL ARTICLE
Sepehr Dehghani-Ghahnaviyeh, Cihan Soylu, Pascal Furet, Camilo Velez-Vega
Phosphatidylinositol-3-kinase Alpha (PI3Kα) is a lipid kinase which regulates signaling pathways involved in cell proliferation. Dysregulation of these pathways promotes several human cancers, pushing for the development of anticancer drugs to target PI3Kα. One such medicinal chemistry campaign at Novartis led to the discovery of BYL719 (Piqray, Alpelicib), a PI3Kα inhibitor approved by the FDA in 2019 for treatment of HR+/HER2-advanced breast cancer with a PIK3CA mutation. Structure-based drug design played a key role in compound design and optimization throughout the discovery process...
February 19, 2024: Journal of Physical Chemistry. B
#23
JOURNAL ARTICLE
Andrin Fluetsch, Elena Di Lascio, Grégori Gerebtzoff, Raquel Rodríguez-Pérez
Medicinal chemistry and drug design efforts can be assisted by machine learning (ML) models that relate the molecular structure to compound properties. Such quantitative structure-property relationship models are generally trained on large data sets that include diverse chemical series (global models). In the pharmaceutical industry, these ML global models are available across discovery projects as an "out-of-the-box" solution to assist in drug design, synthesis prioritization, and experiment selection. However, drug discovery projects typically focus on confined parts of the chemical space (e...
February 19, 2024: Molecular Pharmaceutics
#24
Meenakshi Venkatasubramanian, Leya Schwartz, Nandini Ramachandra, Joshua Bennett, Krithika R Subramanian, Xiaoting Chen, Shanisha Gordon-Mitchell, Ariel Fromowitz, Kith Pradhan, David Shechter, Srabani Sahu, Diane Heiser, Peggy Scherle, Kashish Chetal, Aishwarya Kulkarni, Kasiani C Myers, Matthew T Weirauch, H Leighton Grimes, Daniel T Starczynowski, Amit Verma, Nathan Salomonis
UNLABELLED: The role of splicing dysregulation in cancer is underscored by splicing factor mutations; however, its impact in the absence of such rare mutations is poorly understood. To reveal complex patient subtypes and putative regulators of pathogenic splicing in Acute Myeloid Leukemia (AML), we developed a new approach called OncoSplice. Among diverse new subtypes, OncoSplice identified a biphasic poor prognosis signature that partially phenocopies U2AF1 -mutant splicing, impacting thousands of genes in over 40% of adult and pediatric AML cases...
February 8, 2024: bioRxiv
#25
JOURNAL ARTICLE
Olivier J van Not, Alfons J M van den Eertwegh, John B Haanen, Christian U Blank, Maureen J B Aarts, Jesper van Breeschoten, Franchette W P J van den Berkmortel, Jan-Willem B de Groot, Geke A P Hospers, Rawa K Ismail, Ellen Kapiteijn, Manja Bloem, Melissa M De Meza, Djura Piersma, Rozemarijn S van Rijn, Marion A M Stevense-den Boer, Astrid A M van der Veldt, Gerard Vreugdenhil, Marye J Boers-Sonderen, Willeke A M Blokx, Michel W J M Wouters, Karijn P M Suijkerbuijk
BACKGROUND: The prognosis of advanced melanoma patients has significantly improved over the years. We aimed to evaluate the survival per year of diagnosis. METHODS: All systemically treated patients diagnosed with advanced melanoma from 2013 to 2021 were included from the Dutch Melanoma Treatment Registry. Baseline characteristics and overall survival (OS) were compared between the different years of diagnosis. A multivariable Cox proportional hazards model was used to estimate the association between year of diagnosis and OS...
March 2024: EClinicalMedicine
#26
JOURNAL ARTICLE
René Günther, Claudia Diana Wurster, Svenja Brakemeier, Alma Osmanovic, Olivia Schreiber-Katz, Susanne Petri, Zeljko Uzelac, Miriam Hiebeler, Simone Thiele, Maggie C Walter, Markus Weiler, Tobias Kessler, Maren Freigang, Hanna Sophie Lapp, Isabell Cordts, Paul Lingor, Marcus Deschauer, Andreas Hahn, Kyriakos Martakis, Robert Steinbach, Benjamin Ilse, Annekathrin Rödiger, Julia Bellut, Julia Nentwich, Daniel Zeller, Mohamad Tareq Muhandes, Tobias Baum, Jan Christoph Koch, Bertold Schrank, Sophie Fischer, Andreas Hermann, Christoph Kamm, Steffen Naegel, Alexander Mensch, Markus Weber, Christoph Neuwirth, Helmar C Lehmann, Gilbert Wunderlich, Christian Stadler, Maike Tomforde, Annette George, Martin Groß, Astrid Pechmann, Janbernd Kirschner, Matthias Türk, Mareike Schimmel, Günther Bernert, Pascal Martin, Christian Rauscher, Gerd Meyer Zu Hörste, Petra Baum, Wolfgang Löscher, Marina Flotats-Bastardas, Cornelia Köhler, Kristina Probst-Schendzielorz, Susanne Goldbach, Ulrike Schara-Schmidt, Wolfgang Müller-Felber, Hanns Lochmüller, Otgonzul von Velsen, Christoph Kleinschnitz, Albert C Ludolph, Tim Hagenacker
BACKGROUND: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. METHODS: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022)...
April 2024: The Lancet regional health. Europe
#27
JOURNAL ARTICLE
Markus Trunzer, Joana Teigão, Felix Huth, Birk Poller, Sandrine Desrayaud, Raquel Rodríguez-Pérez, Bernard Faller
It is common practice in drug discovery and development to predict in vivo hepatic clearance from in vitro incubations with liver microsomes or hepatocytes using the well-stirred model (WSM). When applying the WSM to a set of about 3000 Novartis research compounds, 73% of neutral and basic compounds (extended clearance classification system ECCS class 2) were well-predicted within 3-fold. In contrast, only 44% (ECCS class 1A) or 34% (ECCS class 1B) of acids were predicted within 3-fold. To explore the hypothesis whether the higher degree of plasma protein binding for acids contributes to the in vitro in vivo correlation (IVIVC) disconnect, 68 proprietary compounds were incubated with rat liver microsomes (RLM) in the presence and absence of 5% plasma...
February 15, 2024: Drug Metabolism and Disposition: the Biological Fate of Chemicals
#28
Asher Mullard
No abstract text is available yet for this article.
March 2024: Nature Reviews. Drug Discovery
#29
Joshua A Hill, Michael J Martens, Jo-Anne H Young, Kavita Bhavsar, Jianqun Kou, Min Chen, Lik Wee Lee, Aliyah Baluch, Madhav V Dhodapkar, Ryotaro Nakamura, Kristin Peyton, Dianna S Howard, Uroosa Ibrahim, Zainab Shahid, Paul Armistead, Peter Westervelt, John McCarty, Joseph McGuirk, Mehdi Hamadani, Susan DeWolf, Kinga Hosszu, Elad Sharon, Ashley Spahn, Amir A Toor, Stephanie Waldvogel, Lee M Greenberger, Jeffery J Auletta, Mary M Horowitz, Marcie L Riches, Miguel-Angel Perales
BACKGROUND: The optimal timing of vaccination with SARS-CoV-2 vaccines after cellular therapy is incompletely understood. OBJECTIVE: To describe humoral and cellular responses after SARS-CoV-2 vaccination initiated <4 months versus 4-12 months after cellular therapy. DESIGN: Multicenter prospective observational study. SETTING: 34 centers in the United States. PARTICIPANTS: 466 allogeneic hematopoietic cell transplant (HCT; n=231), autologous HCT (n=170), or chimeric antigen receptor T cell (CAR-T cell) therapy (n=65) recipients enrolled between April 2021 and June 2022...
January 25, 2024: medRxiv
#30
MULTICENTER STUDY
Phillip Scheinberg, Carlo Finelli, Efreen H Montaňo-Figueroa, Carlos Vallejo, Lalita Norasetthada, Rodrigo T Calado, Mehmet Turgut, Régis Peffault de Latour, Ulrike Kriemler-Krahn, Jens Haenig, Joan Clark, Junho Jang
BACKGROUND: Antithymocyte globulin (ATG)-based immunosuppression is standard in front-line treatment for people with severe aplastic anaemia without a histocompatible donor or who are 40 years or older. However, ATG requires in-hospital administration, is associated with infusion-related toxicities and has limited availability worldwide. In this study, we investigated the activity and safety of an ATG-free regimen of eltrombopag with cyclosporin A as a potential treatment for patients with severe aplastic anaemia who might not have access to or cannot tolerate horse-ATG...
March 2024: Lancet Haematology
#31
JOURNAL ARTICLE
Eszter Palffy, David John Lewis
Patient Support Programmes (PSPs) are used by the pharmaceutical industry to provide education and support to consumers to overcome the challenges they face managing their condition and treatment. Whilst there is an increasing number of PSPs, limited information is available on whether these programmes contribute to safety signals. PSPs do not have a scientific hypothesis, nor are they governed by a protocol. However, by their nature, PSPs inevitably generate adverse event (AE) reports. The main goal of the research was to gather all Novartis-initiated PSPs for sacubitril/valsartan, followed by research in the company safety database to identify all AE reports emanating from these PSPs...
2024: PloS One
#32
JOURNAL ARTICLE
Bruno Ramos Nascimento, André Dias Nassar Naback, Beatriz Marino Pena Santos, Yvonne Geissbühler, Caroline Demacq, Monica Quijano, Pablo A Perel, Israel Molina, Isis Eloah Machado, Ewerton Cousin, Jonathan F Mosser, Pedro Emanuel de Paula Carvalho, Francisco Rogerlândio Martins-Melo, Antonio Luiz Pinho Ribeiro
BACKGROUND: There is a lack of up-to-date estimates about the prevalence of Chagas disease (ChD) clinical presentations and, therefore, we aimed to assess the prevalence of clinical forms of ChD among seropositive adults, pooling available data. METHODS: A systematic review was conducted in Medline, Embase, Biblioteca Virtual em Saúde and Cochrane databases looking for studies published from 1990 to August 2023, which investigated the prevalence of ChD clinical forms among seropositive adults, including: (i) indeterminate phase, (ii) chronic Chagas cardiomyopathy (CCM), (iii) digestive and (iv) mixed (CCM + digestive) forms...
February 2024: Lancet Reg Health Am
#33
JOURNAL ARTICLE
Melissa P Zundell, Joseph F Merola, Alice B Gottlieb
BACKGROUND: Hidradenitis suppurativa (HS) patients tend to experience diagnosis delay, misdiagnosis, and embarrassment due to their condition. To address these issues, the International Dermatology Outcome Measure (IDEOM) HS Workgroup collaborated with patients to modify an existing Novartis questionnaire to better suit the needs of HS patients. This quality improvement project aimed to use the resulting Shine a Light on HS as Modified by the IDEOM HS Workgroup Questionnaire to enhance communication between HS patients and providers, improve clinical experience for HS patients, and gather relevant demographic data...
February 1, 2024: Journal of Drugs in Dermatology: JDD
#34
JOURNAL ARTICLE
Alec J Sanchez, Sarah Maier, Krishnan Raghavachari
We present a quantum mechanical/machine learning (ML) framework based on random forest to accurately predict the p K a s of complex organic molecules using inexpensive density functional theory (DFT) calculations. By including physics-based features from low-level DFT calculations and structural features from our connectivity-based hierarchy (CBH) fragmentation protocol, we can correct the systematic error associated with DFT. The generalizability and performance of our model are evaluated on two benchmark sets (SAMPL6 and Novartis)...
February 1, 2024: Journal of Chemical Information and Modeling
#35
RANDOMIZED CONTROLLED TRIAL
Nils Venhoff, Wolfgang A Schmidt, Raoul Bergner, Jürgen Rech, Leonore Unger, Hans-Peter Tony, Stephanie Finzel, Ioana Andreica, David M Kofler, Stefan M Weiner, Peter Lamprecht, Hendrik Schulze-Koops, Christine App, Effie Pournara, Meryl H Mendelson, Christian Sieder, Meron Maricos, Jens Thiel
BACKGROUND: The treatment of giant cell arteritis with glucocorticoid-sparing agents is an unmet medical need. We evaluated the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in patients with giant cell arteritis. METHODS: We conducted a Bayesian randomised, parallel-group, double-blind, placebo-controlled, multicentre, phase 2 study at 11 clinics or hospitals in Germany. Patients aged 50 years or older with new-onset or relapsing giant cell arteritis who were naive to biological therapy and already receiving glucocorticoids with a prednisolone equivalent dose of 25-60 mg/day were eligible for inclusion...
June 2023: Lancet Rheumatology
#36
JOURNAL ARTICLE
Antonio Luiz Pinho Ribeiro
Chagas disease (ChD), a Neglected Tropical Disease, has witnessed a transformative epidemiological landscape characterized by a trend of reduction in prevalence, shifting modes of transmission, urbanization, and globalization. Historically a vector-borne disease in rural areas of Latin America, effective control measures have reduced the incidence in many countries, leading to a demographic shift where most affected individuals are now adults. However, challenges persist in regions like the Gran Chaco, and emerging oral transmission in the Amazon basin adds complexity...
2024: Global Heart
#37
JOURNAL ARTICLE
Yrea R J van Rijt-Weetink, Toine C G Egberts, Florence P A M van Hunsel, David J Lewis, Laura M Yates, Ursula Winterfeld, Eugène P van Puijenbroek
BACKGROUND: To assess the causal relationship between a medicinal product and a reported event, relevant information needs to be present. Information elements for assessing cases of exposure to medicinal products during pregnancy were predefined and used in a new tool to assess the quality of information. However, the extent in which the presence or absence of these predefined information elements is associated with the overall clinical quality of these cases, as evaluated by pharmacovigilance experts, remains uncertain...
January 6, 2024: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
#38
JOURNAL ARTICLE
Vasantha Gowda, Mark Atherton, Archana Murugan, Laurent Servais, Jennie Sheehan, Emma Standing, Adnan Manzur, Mariacristina Scoto, Giovanni Baranello, Pinki Munot, Gary McCullagh, Tracey Willis, Sandya Tirupathi, Iain Horrocks, Anil Dhawan, Michael Eyre, Maria Vanegas, Miguel A Fernandez-Garcia, Amy Wolfe, Laura Pinches, Marjorie Illingworth, Marion Main, Lianne Abbott, Hayley Smith, Emily Milton, Sarah D'Urso, Kayal Vijayakumar, Silvia Sanchez Marco, Sinead Warner, Emily Reading, Isobel Douglas, Francesco Muntoni, Min Ong, Anirban Majumdar, Imelda Hughes, Heinz Jungbluth, Elizabeth Wraige
BACKGROUND: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. METHODS: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom...
February 2024: The Lancet regional health. Europe
#39
JOURNAL ARTICLE
Guillaume Favre, Jonathan L Richardson, Alan Moore, Yvonne Geissbühler, Valentine Jehl, Alison Oliver, Svetlana Shechtman, Orna Diav-Citrin, Maya Berlin, Tal De Haan, David Baud, Alice Panchaud, Anil Mor, Meritxell Sabidó, Sabrina de Souza, Christina Chambers, Yrea R J van Rijt-Weetink, Eugène P van Puijenbroek, Laura M Yates, François Girardin, Michael Stellfeld, Ursula Winterfeld
INTRODUCTION AND OBJECTIVE: The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data...
December 19, 2023: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
#40
JOURNAL ARTICLE
SIMPD: an algorithm for generating simulated time splits for validating machine learning approaches.
Gregory A Landrum, Maximilian Beckers, Jessica Lanini, Nadine Schneider, Nikolaus Stiefl, Sereina Riniker
Time-split cross-validation is broadly recognized as the gold standard for validating predictive models intended for use in medicinal chemistry projects. Unfortunately this type of data is not broadly available outside of large pharmaceutical research organizations. Here we introduce the SIMPD (simulated medicinal chemistry project data) algorithm to split public data sets into training and test sets that mimic the differences observed in real-world medicinal chemistry project data sets. SIMPD uses a multi-objective genetic algorithm with objectives derived from an extensive analysis of the differences between early and late compounds in more than 130 lead-optimization projects run within the Novartis Institutes for BioMedical Research...
December 11, 2023: Journal of Cheminformatics
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