The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer

Cell Proliferation, Journal Year: 2003, Volume and Issue: 36(3), P. 131 - 149

Published: June 1, 2003

Abstract. The cell cycle is controlled by numerous mechanisms ensuring correct division. This review will focus on these mechanisms, i.e. regulation of cyclin‐dependent kinases (CDK) cyclins, CDK inhibitors and phosphorylating events. quality checkpoints activated after DNA damage are also discussed. complexity the reflected in different alterations leading to aberrant proliferation development cancer. Consequently, targeting general particular presents unique opportunities for drug discovery. provides an overview deregulation Different families known acting ATP competition Currently, at least three compounds with inhibitory activity (flavopiridol, UCN‐01, roscovitine) have entered clinical trials.

Language: Английский

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Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

New England Journal of Medicine, Journal Year: 2019, Volume and Issue: 381(19), P. 1809 - 1819

Published: Oct. 31, 2019

Cystic fibrosis is caused by mutations in the gene encoding cystic transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy Phe508del CFTR mutation. In a phase 2 trial involving who were heterozygous for mutation minimal-function (Phe508del-minimal function genotype), next-generation corrector elexacaftor, combination with tezacaftor ivacaftor, improved clinical outcomes.We conducted 3, randomized, double-blind, placebo-controlled to confirm efficacy safety elexacaftor-tezacaftor-ivacaftor 12 years age or older Phe508del-minimal genotypes. Patients randomly assigned receive placebo 24 weeks. The primary end point was absolute change from baseline percentage predicted forced expiratory volume 1 second (FEV1) week 4.A total 403 underwent randomization received dose active treatment placebo. Elexacaftor-tezacaftor-ivacaftor, relative placebo, resulted FEV1 that 13.8 points higher 4 weeks 14.3 through weeks, rate pulmonary exacerbations 63% lower, respiratory domain score on Fibrosis Questionnaire-Revised (range, 0 100, scores indicating patient-reported quality life regard symptoms; minimum clinically important difference, points) 20.2 higher, sweat chloride concentration 41.8 mmol per liter lower (P<0.001 all comparisons). Elexacaftor-tezacaftor-ivacaftor generally safe had an acceptable side-effect profile. Most adverse events mild moderate. Adverse leading discontinuation regimen occurred 1% group.Elexacaftor-tezacaftor-ivacaftor efficacious genotypes, whom previous modulator regimens ineffective. (Funded Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).

Language: Английский

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Cell cycle proteins as promising targets in cancer therapy

Nature reviews. Cancer, Journal Year: 2017, Volume and Issue: 17(2), P. 93 - 115

Published: Jan. 27, 2017

Language: Английский

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Inflammatory Bowel Disease

Annual Review of Immunology, Journal Year: 2010, Volume and Issue: 28(1), P. 573 - 621

Published: March 1, 2010

Insights into inflammatory bowel disease (IBD) are advancing rapidly owing to immunologic investigations of a plethora animal models intestinal inflammation, ground-breaking advances in the interrogation diseases that inherited as complex genetic traits, and development culture-independent methods define composition microbiota. These bringing deeper understanding genetically determined interplay between commensal microbiota, epithelial cells, immune system manner which this might be modified by relevant environmental factors pathogenesis IBD. This review examines these interactions and, where possible, potential lessons from IBD-directed, biologic therapies may allow for elucidation pathways central humans.

Language: Английский

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Targeting potential drivers of COVID-19: Neutrophil extracellular traps

The Journal of Experimental Medicine, Journal Year: 2020, Volume and Issue: 217(6)

Published: April 14, 2020

Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory that in ∼10-15% of patients progresses to acute distress syndrome (ARDS) triggered by cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis little known yet powerful function neutrophils-the ability form neutrophil extracellular traps (NETs)-may contribute organ damage mortality COVID-19. We show lung infiltration neutrophils an specimen from patient who succumbed discuss prior reports linking aberrant NET formation pulmonary diseases, thrombosis, mucous secretions airways, production. If our correct, targeting NETs directly and/or indirectly with existing drugs may reduce clinical severity

Language: Английский

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Neutrophil extracellular traps in COVID-19

JCI Insight, Journal Year: 2020, Volume and Issue: unknown

Published: April 24, 2020

In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are webs chromatin, microbicidal proteins, and oxidant enzymes that released by neutrophils contain infections. However, when not properly regulated, NETs have the potential propagate inflammation microvascular thrombosis — including in lungs patients with acute distress syndrome. We now report sera from COVID-19 elevated levels cell-free DNA, myeloperoxidase-DNA (MPO-DNA), citrullinated histone H3 (Cit-H3); latter 2 specific markers NETs. Highlighting clinical relevance these findings, DNA strongly correlated acute-phase reactants, C-reactive protein, D-dimer, lactate dehydrogenase, as well absolute neutrophil count. MPO-DNA associated both count, while Cit-H3 platelet levels. Importantly, were higher hospitalized receiving mechanical ventilation compared breathing room air. Finally, individuals triggered NET release control vitro. Future studies should investigate predictive power circulating longitudinal cohorts determine extent which may be novel therapeutic targets COVID-19.

Language: Английский

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Targeting microbial biofilms: current and prospective therapeutic strategies

Nature Reviews Microbiology, Journal Year: 2017, Volume and Issue: 15(12), P. 740 - 755

Published: Sept. 25, 2017

Language: Английский

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Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture

Nature Methods, Journal Year: 2015, Volume and Issue: 12(7), P. 671 - 678

Published: May 25, 2015

Language: Английский

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The specificities of protein kinase inhibitors: an update

Biochemical Journal, Journal Year: 2003, Volume and Issue: 371(1), P. 199 - 204

Published: March 26, 2003

We have previously examined the specificities of 28 commercially available compounds, reported to be relatively selective inhibitors particular serine/threonine-specific protein kinases [Davies, Reddy, Caivano and Cohen (2000) Biochem. J. 351, 95—105]. In present study, we extended this analysis a further 14 compounds. Of these, indirubin-3′-monoxime, SP 600125, KT 5823 ML-9 were found inhibit number conclusions drawn from their use in cell-based assays are likely erroneous. Kenpaullone, Alsterpaullone, Purvalanol, Roscovitine, pyrazolopyrimidine 1 (PP1), PP2 ML-7 more specific, but still inhibited two or with similar potency. Our results suggest that combined Roscovitine Kenpaullone may useful for identifying substrates physiological roles cyclin-dependent kinases, whereas LiCl glycogen synthase kinase 3. The SU 6656 either PP1 Src family members. Epigallocatechin 3-gallate, one main polyphenolic constituents tea, panel, dual-specificity, tyrosine-phosphorylated regulated 1A (DYRK1A; IC50 = 0.33μM) p38-regulated/activated (PRAK; 1.0μM).

Language: Английский

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Generation of pathogenic TH17 cells in the absence of TGF-β signalling

Nature, Journal Year: 2010, Volume and Issue: 467(7318), P. 967 - 971

Published: Oct. 1, 2010

Language: Английский

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