Aging is the main risk factor for most chronic diseases, disabilities, and declining health. It has been proposed that senescent cells—damaged cells that have lost the ability to divide—drive the ...deterioration that underlies aging and age‐related diseases. However, definitive evidence for this relationship has been lacking. The use of a progeroid mouse model (which expresses low amounts of the mitotic checkpoint protein BubR1) has been instrumental in demonstrating that p16Ink4a‐positive senescent cells drive age‐related pathologies and that selective elimination of these cells can prevent or delay age‐related deterioration. These studies identify senescent cells as potential therapeutic targets in the treatment of aging and age‐related diseases. Here, we describe how senescent cells develop, the experimental evidence that causally implicates senescent cells in age‐related dysfunction, the chronic diseases and disorders that are characterized by the accumulation of senescent cells at sites of pathology, and the therapeutic approaches that could specifically target senescent cells.
Clinical Pharmacology & Therapeutics (2013); 93 1, 105–116. doi:10.1038/clpt.2012.193
Mitigating the risks of antibiotic resistance requires a horizon scan linking the quality with the quantity of data reported on drivers of antibiotic resistance in humans, arising from the human, ...animal, and environmental reservoirs. We did a systematic review using a One Health approach to survey the key drivers of antibiotic resistance in humans. Two sets of reviewers selected 565 studies from a total of 2819 titles and abstracts identified in Embase, MEDLINE, and Scopus (2005–18), and the European Centre for Disease Prevention and Control, the US Centers for Disease Control and Prevention, and WHO (One Health data). Study quality was assessed in accordance with Cochrane recommendations. Previous antibiotic exposure, underlying disease, and invasive procedures were the risk factors with most supporting evidence identified from the 88 risk factors retrieved. The odds ratios of antibiotic resistance were primarily reported to be between 2 and 4 for these risk factors when compared with their respective controls or baseline risk groups. Food-related transmission from the animal reservoir and water-related transmission from the environmental reservoir were frequently quantified. Uniformly quantifying relationships between risk factors will help researchers to better understand the process by which antibiotic resistance arises in human infections.
Antibiotic resistance poses a threat to public health and healthcare systems. Escherichia coli causes more bacteraemia episodes in England than any other bacterial species. This study aimed to ...estimate the burden of E. coli bacteraemia and associated antibiotic resistance in the secondary care setting.
This was a retrospective cohort study, with E. coli bacteraemia as the main exposure of interest. Adult hospital in-patients, admitted to acute NHS hospitals between July 2011 and June 2012 were included. English national surveillance and administrative datasets were utilised. Cox proportional hazard, subdistribution hazard and multistate models were constructed to estimate rate of discharge, rate of in-hospital death and excess length of stay, with a unit bed day cost applied to the latter to estimate cost burden from the healthcare system perspective.
14,042 E. coli bacteraemia and 8,919,284 non-infected inpatient observations were included. E. coli bacteraemia was associated with an increased rate of in-hospital death across all models, with an adjusted subdistribution hazard ratio of 5.88 (95% CI: 5.62-6.15). Resistance was not found to be associated with in-hospital mortality once adjusting for patient and hospital covariates. However, resistance was found to be associated with an increased excess length of stay. This was especially true for third generation cephalosporin (1.58 days excess length of stay, 95% CI: 0.84-2.31) and piperacillin/tazobactam resistance (1.23 days (95% CI: 0.50-1.95)). The annual cost of E. coli bacteraemia was estimated to be £14,346,400 (2012 £), with third-generation cephalosporin resistance associated with excess costs per infection of £420 (95% CI: 220-630).
E. coli bacteraemia places a statistically significant burden on patient health and the hospital sector in England. Resistance to front-line antibiotics increases length of stay; increasing the cost burden of such infections in the secondary care setting.
•The pursuit of ‘undruggable’ therapeutic targets has reinvigorated interest in natural products.•Peptides have been traditionally considered poor pharmaceutical candidates.•Some large cyclic peptide ...natural products have proven bioactivity and oral bioavailability.•Cyclic peptides have been synthesized to explore ADME optimization.•New and optimized chemical structures are shown to achieve unprecedented oral bioavailability.
As interest in protein–protein interactions and other previously-undruggable targets increases, medicinal chemists are returning to natural products for design inspiration toward molecules that transcend the paradigm of small molecule drugs. These compounds, especially peptides, often have poor ADME properties and thus require a more nuanced understanding of structure-property relationships to achieve desirable oral bioavailability. Although there have been few clinical successes in this chemical space to date, recent work has identified opportunities to introduce favorable physicochemical properties to peptidic macrocycles that maintain activity and oral bioavailability.
Accurate estimates of the burden of antimicrobial resistance (AMR) are needed to establish the magnitude of this global threat in terms of both health and cost, and to paramaterise cost-effectiveness ...evaluations of interventions aiming to tackle the problem. This review aimed to establish the alternative methodologies used in estimating AMR burden in order to appraise the current evidence base.
MEDLINE, EMBASE, Scopus, EconLit, PubMed and grey literature were searched. English language studies evaluating the impact of AMR (from any microbe) on patient, payer/provider and economic burden published between January 2013 and December 2015 were included. Independent screening of title/abstracts followed by full texts was performed using pre-specified criteria. A study quality score (from zero to one) was derived using Newcastle-Ottawa and Philips checklists. Extracted study data were used to compare study method and resulting burden estimate, according to perspective. Monetary costs were converted into 2013 USD.
Out of 5187 unique retrievals, 214 studies were included. One hundred eighty-seven studies estimated patient health, 75 studies estimated payer/provider and 11 studies estimated economic burden. 64% of included studies were single centre. The majority of studies estimating patient or provider/payer burden used regression techniques. 48% of studies estimating mortality burden found a significant impact from resistance, excess healthcare system costs ranged from non-significance to $1 billion per year, whilst economic burden ranged from $21,832 per case to over $3 trillion in GDP loss. Median quality scores (interquartile range) for patient, payer/provider and economic burden studies were 0.67 (0.56-0.67), 0.56 (0.46-0.67) and 0.53 (0.44-0.60) respectively.
This study highlights what methodological assumptions and biases can occur dependent on chosen outcome and perspective. Currently, there is considerable variability in burden estimates, which can lead in-turn to inaccurate intervention evaluations and poor policy/investment decisions. Future research should utilise the recommendations presented in this review.
This systematic review is registered with PROSPERO (PROSPERO CRD42016037510).
Radiotherapy has been used for more than a hundred years to cure or locally control tumors. Regression of tumors outside of the irradiated field was occasionally observed and is known as the abscopal ...effect. However, the occurrence of systemic anti-tumor effects was deemed too rare and unpredictable to be a therapeutic goal. Recent studies suggest that immunotherapy and radiation in combination may enhance the abscopal response. Increasing numbers of cases are being reported since the routine implementation of immune checkpoint inhibitors, showing that combined radiotherapy with immunotherapy has a synergistic effect on both local and distant (i.e., unirradiated) tumors. In this review, we summarize pre-clinical and clinical reports, with a specific focus on the mechanisms behind the immunostimulatory effects of radiation and how this is enhanced by immunotherapy.
Conformational ensembles of eight cyclic hexapeptide diastereomers in explicit cyclohexane, chloroform, and water were analyzed by multicanonical molecular dynamics (McMD) simulations. Free-energy ...landscapes (FELs) for each compound and solvent were obtained from the molecular shapes and principal component analysis at T = 300 K; detailed analysis of the conformational ensembles and flexibility of the FELs revealed that permeable compounds have different structural profiles even for a single stereoisomeric change. The average solvent-accessible surface area (SASA) in cyclohexane showed excellent correlation with the cell permeability, whereas this correlation was weaker in chloroform. The average SASA in water correlated with the aqueous solubility. The average polar surface area did not correlate with cell permeability in these solvents. A possible strategy for designing permeable cyclic peptides from FELs obtained from McMD simulations is proposed.
As drug discovery moves increasingly toward previously “undruggable” targets such as protein–protein interactions, lead compounds are becoming larger and more lipophilic. Although increasing ...lipophilicity can improve membrane permeability, it can also incur serious liabilities, including poor water solubility, increased toxicity, and faster metabolic clearance. Here we introduce a new efficiency metric, especially relevant to “beyond rule of 5” molecules, that captures, in a simple, unitless value, these opposing effects of lipophilicity on molecular properties. Lipophilic permeability efficiency (LPE) is defined as log D 7.4 dec/w – m lipocLogP + b scaffold, where log D 7.4 dec/w is the experimental decadiene–water distribution coefficient (pH 7.4), cLogP is the calculated octanol–water partition coefficient, and m lipo and b scaffold are scaling factors to standardize LPE values across different cLogP metrics and scaffolds. Using a variety of peptidic and nonpeptidic macrocycle drugs, we show that LPE provides a functional assessment of the efficiency with which a compound achieves passive membrane permeability at a given lipophilicity.
Nutrient Imbalances in Agricultural Development Vitousek, P.M; Naylor, R; Crews, T ...
Science (American Association for the Advancement of Science),
06/2009, Letnik:
324, Številka:
5934
Journal Article
Recenzirano
Nutrient additions to intensive agricultural systems range from inadequate to excessive--and both extremes have substantial human and environmental costs.
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