Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As ...a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017.
We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990–2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates.
In 2017, an estimated 48·9 million (95% uncertainty interval UI 38·9–62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1–12·0) sepsis-related deaths were reported, representing 19·7% (18·2–21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8–54·5) and mortality decreased by 52·8% (47·7–57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia.
Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa.
The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children's Hospital Foundation, the Wellcome Trust, and the Fleming Fund.
What’s a good fragment? Fragment‐based drug discovery is well‐established within many pharmaceutical, biotech, and academic institutions for generating new drugs. In this Essay, the opportunities and ...challenges for organic chemists to design and synthesize new fragments are described.
Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic ...alterations in FGF receptor (
) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which is associated with prolonged inhibition of FGFR signaling, possibly due to sustained release of the inhibitor. In xenografts from human tumor cell lines or patient-derived tumor tissue with activating FGFR alterations, JNJ-42756493 administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors. The results of the current study provide a strong rationale for the clinical investigation of JNJ-42756493 in patients with tumors harboring FGFR pathway alterations.
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The search for new drugs is plagued by high attrition rates at all stages in research and development. Chemists have an opportunity to tackle this problem because attrition can be traced back, in ...part, to the quality of the chemical leads. Fragment-based drug discovery (FBDD) is a new approach, increasingly used in the pharmaceutical industry, for reducing attrition and providing leads for previously intractable biological targets. FBDD identifies low-molecular-weight ligands (∼150 Da) that bind to biologically important macromolecules. The three-dimensional experimental binding mode of these fragments is determined using X-ray crystallography or NMR spectroscopy, and is used to facilitate their optimization into potent molecules with drug-like properties. Compared with high-throughput-screening, the fragment approach requires fewer compounds to be screened, and, despite the lower initial potency of the screening hits, offers more efficient and fruitful optimization campaigns. Here, we review the rise of FBDD, including its application to discovering clinical candidates against targets for which other chemistry approaches have struggled.
Large-scale sequencing of human tumours has uncovered a vast array of genomic alterations. Genetically engineered mouse models recapitulate many features of human cancer and have been instrumental in ...assigning biological meaning to specific cancer-associated alterations. However, their time, cost and labour-intensive nature limits their broad utility; thus, the functional importance of the majority of genomic aberrations in cancer remains unknown. Recent advances have accelerated the functional interrogation of cancer-associated alterations within in vivo models. Specifically, the past few years have seen the emergence of CRISPR-Cas9-based strategies to rapidly generate increasingly complex somatic alterations and the development of multiplexed and quantitative approaches to ascertain gene function in vivo.
The initiation of cell division integrates a large number of intra- and extracellular inputs. D-type cyclins (hereafter, cyclin D) couple these inputs to the initiation of DNA replication
. Increased ...levels of cyclin D promote cell division by activating cyclin-dependent kinases 4 and 6 (hereafter, CDK4/6), which in turn phosphorylate and inactivate the retinoblastoma tumour suppressor. Accordingly, increased levels and activity of cyclin D-CDK4/6 complexes are strongly linked to unchecked cell proliferation and cancer
. However, the mechanisms that regulate levels of cyclin D are incompletely understood
. Here we show that autophagy and beclin 1 regulator 1 (AMBRA1) is the main regulator of the degradation of cyclin D. We identified AMBRA1 in a genome-wide screen to investigate the genetic basis of the response to CDK4/6 inhibition. Loss of AMBRA1 results in high levels of cyclin D in cells and in mice, which promotes proliferation and decreases sensitivity to CDK4/6 inhibition. Mechanistically, AMBRA1 mediates ubiquitylation and proteasomal degradation of cyclin D as a substrate receptor for the cullin 4 E3 ligase complex. Loss of AMBRA1 enhances the growth of lung adenocarcinoma in a mouse model, and low levels of AMBRA1 correlate with worse survival in patients with lung adenocarcinoma. Thus, AMBRA1 regulates cellular levels of cyclin D, and contributes to cancer development and the response of cancer cells to CDK4/6 inhibitors.
Experiences in fragment-based drug discovery Murray, Christopher W; Verdonk, Marcel L; Rees, David C
Trends in pharmacological sciences (Regular ed.),
05/2012, Letnik:
33, Številka:
5
Journal Article
Recenzirano
Fragment-based drug discovery (FBDD) has become established in both industry and academia as an alternative approach to high-throughput screening for the generation of chemical leads for drug ...targets. In FBDD, specialised detection methods are used to identify small chemical compounds (fragments) that bind to the drug target, and structural biology is usually employed to establish their binding mode and to facilitate their optimisation. In this article, we present three recent and successful case histories in FBDD. We then re-examine the key concepts and challenges of FBDD with particular emphasis on recent literature and our own experience from a substantial number of FBDD applications. Our opinion is that careful application of FBDD is living up to its promise of delivering high quality leads with good physical properties and that in future many drug molecules will be derived from fragment-based approaches.
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•Crystallographic screening using high-concentration, aqueous, soaks with a library of ultra-low-molecular-weight compounds (MiniFrags).•Identification of protein, ligand-binding, hot ...and warm spots to inform medicinal chemistry design strategy.•Enhanced sampling of chemical space and detection of unprecedented ligand binding pockets with MiniFrags.
We present a novel crystallographic screening methodology (MiniFrags) that employs high-concentration aqueous soaks with a chemically diverse and ultra-low-molecular-weight library (heavy atom count 5–7) to identify ligand-binding hot and warm spots on proteins. We propose that MiniFrag screening represents a highly effective method for guiding optimisation of fragment-derived lead compounds or chemical tools and that the high screening hit rates reflect enhanced sampling of chemical space.
Fragment-based ligand screening is now established as an emerging paradigm for drug discovery. Here we examine the recent literature looking at how structural biology has been used in a variety of ...successful fragment-screening applications. We argue that the determination of experimental binding modes has proved to be one of the mainstays of successful fragment-based approaches and that this reflects the difficulty in optimising a fragment to a lead molecule in the absence of structural information. We focus on antimicrobial research where fragment-based drug discovery allows control of the physical properties of the emerging lead molecule.
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