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BACKGROUND: Population-based register data could be used to improve our knowledge of patients surgically treated for foot and ankle disorders. The quality register Swefoot was recently created to collect surgical and patient-reported data of foot and ankle surgery. This manuscript aims to describe the development and current use of the register. METHODS: The development of Swefoot started in 2014 and currently, data on 16 different diagnoses are collected in 49 units performing foot and ankle surgery. Registrations are performed by the surgeon and the patient. RESULTS: Between 2014 and 2020 approximately 20,000 surgical procedures have been registered. 75.1% of the registered patients were women, 9.3% were smokers, 9.3% had a concomitant rheumatoid disease, and 18.4% a BMI larger than 30 kg/m2. CONCLUSIONS: The Swefoot is a unique national register for foot and ankle surgery. It is by now possible to present demographic, surgical, and outcome parameters based on Swefoot.
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Extremidade Inferior , Humanos , Feminino , Masculino , Autorrelato , Sistema de Registros , Suécia/epidemiologiaRESUMO
Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer and Alzheimer's disease, supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we have described the discovery and profile of 8l (ARUK3001185) as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identified 6a and 6b as a pair of outstanding hits. Fragment development of 6 delivered 8l that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8l to be selective against serine hydrolases, kinases, and drug targets.
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Inibidores Enzimáticos , Esterases , Encéfalo/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Esterases/metabolismo , Via de Sinalização WntRESUMO
Supressed levels of intracellular cAMP have been associated with malignancy. Thus, elevating cAMP through activation of adenylyl cyclase (AC) or by inhibition of phosphodiesterase (PDE) may be therapeutically beneficial. Here, we demonstrate that elevated cAMP levels suppress growth in C6 cells (a model of glioma) through treatment with forskolin, an AC activator, or a range of small molecule PDE inhibitors with differing selectivity profiles. Forskolin suppressed cell growth in a PKA-dependent manner by inducing a G2/M phase cell cycle arrest. In contrast, trequinsin (a non-selective PDE2/3/7 inhibitor), not only inhibited cell growth via PKA, but also stimulated (independent of PKA) caspase-3/-7 and induced an aneuploidy phenotype. Interestingly, a cocktail of individual PDE 2,3,7 inhibitors suppressed cell growth in a manner analogous to forskolin but not trequinsin. Finally, we demonstrate that concomitant targeting of both AC and PDEs synergistically elevated intracellular cAMP levels thereby potentiating their antiproliferative actions.
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Proliferação de Células/fisiologia , AMP Cíclico/metabolismo , Glioma/metabolismo , Inibidores do Crescimento/farmacologia , Líquido Intracelular/metabolismo , Adenilil Ciclases/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colforsina/farmacologia , Glioma/patologia , Humanos , Líquido Intracelular/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , RatosRESUMO
Glioblastoma (GBM) remains one of the most intransigent of cancers, with a median overall survival of only 15 months after diagnosis. Drug treatments have largely proven ineffective; it is thought that this is related to the heterogeneous nature and plasticity of GBM-initiating stem cell lineages. Although many combination drug therapies are being positioned to address tumour heterogeneity, the most promising therapeutic approaches for GBM to date appear to be those targeting GBM by vaccination or antibody- and cell-based immunotherapy. We review the most recent clinical trials for GBM and discuss the role of adaptive clinical trials in developing personalised treatment strategies to address intra- and inter-tumoral heterogeneity.
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Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos , HumanosRESUMO
Glioblastoma is the most common and malignant form of brain cancer, for which the standard treatment is maximal surgical resection, radiotherapy and chemotherapy. Despite these interventions, mean overall survival remains less than 15 months, during which extensive tumor infiltration throughout the brain occurs. The resulting metastasized cells in the brain are characterized by chemotherapy resistance and extensive intratumoral heterogeneity. An orthogonal approach attacking both intracellular resistance mechanisms as well as intercellular heterogeneity is necessary to halt tumor progression. For this reason, we established the WINDOW Consortium (Window for Improvement for Newly Diagnosed patients by Overcoming disease Worsening), in which we are establishing a strategy for rational selection and development of effective therapies against glioblastoma. Here, we overview the many challenges posed in treating glioblastoma, including selection of drug combinations that prevent therapy resistance, the need for drugs that have improved blood brain barrier penetration and strategies to counter heterogeneous cell populations within patients. Together, this forms the backbone of our strategy to attack glioblastoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Sistemas de Liberação de Medicamentos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/efeitos adversosRESUMO
INTRODUCTION: Glioblastoma multiforme (GBM) is the most common and aggressive malignant glioma, with patients having a median survival of just over one year. Current chemotherapies, with surgery and radiotherapy, provide only minor patient benefit. There is a great need to discover and develop novel therapies for this devastating disease. Areas covered: Expert opinion: AREAS COVERED: The patent literature reveals novel therapies, providing insights into emerging GBM therapeutics. We have used the Google and USPTO patent databases to generate a detailed landscape of patents and patent applications from companies active in the areas of glioma and/or GBM. Specific patents have been grouped into six areas: novel compounds; treatments and therapeutic targets; combination therapies; immunotherapies; delivery methods; and biomarkers for diagnosis and prognosis. EXPERT OPINION: There has been a steady increase in the number of patents on GBM over the last five years. Despite many new compounds being developed and patented for a broad range of cancers, only a small percentage of these are specifically targeted to GBM. Notable trends in the patent literature include both the development of combination therapies to combat the heterogeneous nature of GBM, and the use of immunotherapies building on the promise of cancer vaccines and CAR T-cell therapy.
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Antineoplásicos/administração & dosagem , Glioblastoma/tratamento farmacológico , Glioma/tratamento farmacológico , Animais , Biomarcadores Tumorais/metabolismo , Vacinas Anticâncer/administração & dosagem , Desenho de Fármacos , Glioblastoma/patologia , Glioma/patologia , Humanos , Imunoterapia/métodos , Patentes como Assunto , PrognósticoRESUMO
Summary: In this work, we present eMolTox, a web server for the prediction of potential toxicity associated with a given molecule. A total of 174 toxicology-related in vitro/vivo experimental datasets were used for model construction and Mondrian conformal prediction was used to estimate the confidence of the resulting predictions. Toxic substructure analysis is also implemented in eMolTox. eMolTox predicts and displays a wealth of information of potential molecular toxicities for safety analysis in drug development. Availability and implementation: The eMolTox Server is freely available for use on the web at http://xundrug.cn/moltox. Supplementary information: Supplementary data are available at Bioinformatics online.
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Software , Toxicologia/métodos , Animais , Carcinógenos/toxicidade , Humanos , Mutagênicos/toxicidadeRESUMO
Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity at multiple targets is required to produce a clinical effect. In particular, suitable compounds may be useful in treating neurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity at the adenosine A1 and A2A receptors (A1R and A2AR) and phosphodiesterase 10A (PDE10A), which modulate intracellular cAMP levels. Hence, in this work we describe a computational method for the design of synthetically feasible ligands that bind to A1 and A2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosynthetic approach employing in silico target prediction and docking, which may be generally applicable to multi-target compound design at several target classes. This approach has identified 2-aminopyridine-3-carbonitriles as the first multi-target ligands at A1R, A2AR and PDE10A, by showing agreement between the ligand and structure based predictions at these targets. The series were synthesized via an efficient one-pot scheme and validated pharmacologically as A1R/A2AR-PDE10A ligands, with IC50 values of 2.4-10.0 µM at PDE10A and Ki values of 34-294 nM at A1R and/or A2AR. Furthermore, selectivity profiling of the synthesized 2-amino-pyridin-3-carbonitriles against other subtypes of both protein families showed that the multi-target ligand 8 exhibited a minimum of twofold selectivity over all tested off-targets. In addition, both compounds 8 and 16 exhibited the desired multi-target profile, which could be considered for further functional efficacy assessment, analog modification for the improvement of selectivity towards A1R, A2AR and PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels.
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Transition state and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study, a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over 5 million compounds, and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction.