Summary Background Assessment of progress in cancer control at the population level is increasingly important. Population-based survival trends provide a key insight into the overall effectiveness of ...the health system, alongside trends in incidence and mortality. For this purpose, we aimed to provide a unique measure of cancer survival. Methods In this observational study, we analysed trends in survival with population-based data for 7·2 million adults diagnosed with a first, primary, invasive malignancy in England and Wales during 1971–2011 and followed up to the end of 2012. We constructed a survival index for all cancers combined using data from the National Cancer Registry and the Welsh Cancer Intelligence and Surveillance Unit. The index is designed to be independent of changes in the age distribution of patients with cancer and of changes in the proportion of lethal cancers in each sex. We analysed trends in the cancer survival index at 1, 5, and 10 years after diagnosis for the selected periods 1971–72, 1980–81, 1990–91, 2000–01, 2005–06, and 2010–11. We also estimated trends in age-sex-adjusted survival for each cancer. We define the difference in net survival between the oldest (75–99 years) and youngest (15–44 years) patients as the age gap in survival. We evaluated the absolute change (%) in the age gap since 1971. Findings The overall index of net survival increased substantially during the 40-year period 1971–2011, both in England and in Wales. For patients diagnosed in 1971–72, the index of net survival was 50% at 1 year after diagnosis. 40 years later, the same value of 50% was predicted at 10 years after diagnosis. The average 10% survival advantage for women persisted throughout this period. Predicted 10-year net survival adjusted for age and sex for patients diagnosed between 2010 and 2011 ranged from 1·1% for pancreatic cancer to 98·2% for testicular cancer. Net survival for the oldest patients (75–99 years) was persistently lower than for the youngest (15–44 years), even after adjustment for the much higher mortality from causes other than cancer in elderly people. Interpretation These findings support substantial increases in both short-term and long-term net survival from all cancers combined in both England and Wales. The net survival index provides a convenient, single number that summarises the overall patterns of cancer survival in any one population, in each calendar period, for young and old men and women and for a wide range of cancers with very disparate survival. The persistent sex difference is partly due to a more favourable cancer distribution in women than men. The very wide differences in survival for different cancers, and the persistent age gap in survival, suggest the need for renewed efforts to improve cancer outcomes. Future monitoring of the cancer survival index will not be possible unless the current crisis of public concern about sharing of individual data for public health research can be resolved. Funding Cancer Research UK.
Summary Millions of people will continue to be diagnosed with cancer every year for the foreseeable future. These patients all need access to optimum health care. Population-based cancer survival is ...a key measure of the overall effectiveness of health systems in management of cancer. Survival varies very widely around the world. Global surveillance of cancer survival is needed, because unless these avoidable inequalities are measured, and reported on regularly, nothing will be done explicitly to reduce them.
The molecular triggers for axon degeneration remain unknown. We identify endogenous Nmnat2 as a labile axon survival factor whose constant replenishment by anterograde axonal transport is a limiting ...factor for axon survival. Specific depletion of Nmnat2 is sufficient to induce Wallerian-like degeneration of uninjured axons which endogenous Nmnat1 and Nmnat3 cannot prevent. Nmnat2 is by far the most labile Nmnat isoform and is depleted in distal stumps of injured neurites before Wallerian degeneration begins. Nmnat2 turnover is equally rapid in injured Wld(S) neurites, despite delayed neurite degeneration, showing it is not a consequence of degeneration and also that Wld(S) does not stabilize Nmnat2. Depletion of Nmnat2 below a threshold level is necessary for axon degeneration since exogenous Nmnat2 can protect injured neurites when expressed at high enough levels to overcome its short half-life. Furthermore, proteasome inhibition slows both Nmnat2 turnover and neurite degeneration. We conclude that endogenous Nmnat2 prevents spontaneous degeneration of healthy axons and propose that, when present, the more long-lived, functionally related Wld(S) protein substitutes for Nmnat2 loss after axon injury. Endogenous Nmnat2 represents an exciting new therapeutic target for axonal disorders.
Traumatic axonal injury (TAI) is an important pathoanatomical subgroup of traumatic brain injury (TBI) and a major driver of mortality and functional impairment. Experimental models have provided ...insights into the effects of mechanical deformation on the neuronal cytoskeleton and the subsequent processes that drive axonal injury. There is also increasing recognition that axonal or white matter loss may progress for years post-injury and represent one mechanistic framework for progressive neurodegeneration after TBI. Previous trials of novel therapies have failed to make an impact on clinical outcome, in both TBI in general and TAI in particular. Recent advances in understanding the cellular and molecular mechanisms of injury have the potential to translate into novel therapeutic targets.
Rapid and accurate profiling of infection-causing pathogens remains a significant challenge in modern health care. Despite advances in molecular diagnostic techniques, blood culture analysis remains ...the gold standard for diagnosing sepsis. However, this method is too slow and cumbersome to significantly influence the initial management of patients. The swift initiation of precise and targeted antibiotic therapies depends on the ability of a sepsis diagnostic test to capture clinically relevant organisms along with antimicrobial resistance within 1 to 3 h. The administration of appropriate, narrow-spectrum antibiotics demands that such a test be extremely sensitive with a high negative predictive value. In addition, it should utilize small sample volumes and detect polymicrobial infections and contaminants. All of this must be accomplished with a platform that is easily integrated into the clinical workflow. In this review, we outline the limitations of routine blood culture testing and discuss how emerging sepsis technologies are converging on the characteristics of the ideal sepsis diagnostic test. We include seven molecular technologies that have been validated on clinical blood specimens or mock samples using human blood. In addition, we discuss advances in machine learning technologies that use electronic medical record data to provide contextual evaluation support for clinical decision-making.
SARM1 function and nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) loss both promote axon degeneration, but their relative relationship in the process is unknown. Here, we show that NMNAT2 ...loss and resultant changes to NMNAT metabolites occur in injured SARM1-deficient axons despite their delayed degeneration and that axon degeneration specifically induced by NMNAT2 depletion requires SARM1. Strikingly, SARM1 deficiency also corrects axon outgrowth in mice lacking NMNAT2, independently of NMNAT metabolites, preventing perinatal lethality. Furthermore, NAMPT inhibition partially restores outgrowth of NMNAT2-deficient axons, suggesting that the NMNAT substrate, NMN, contributes to this phenotype. NMNAT2-depletion-dependent degeneration of established axons and restricted extension of developing axons are thus both SARM1 dependent, and SARM1 acts either downstream of NMNAT2 loss and NMN accumulation in a linear pathway or in a parallel branch of a convergent pathway. Understanding the pathway will help establish relationships with other modulators of axon survival and facilitate the development of effective therapies for axonopathies.
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•SARM1 is required for WLDS-sensitive axon degeneration caused by NMNAT2 depletion•SARM1 deficiency rescues developmental axon defects caused by a lack of NMNAT2•Mice lacking NMNAT2 and SARM1 are viable•Lowering NMN by inhibiting NAMPT partially rescues growth of NMNAT2-deficient axons
Gilley et al. find that SARM1 promotes axon degeneration after NMNAT2 depletion and limits outgrowth of axons constitutively lacking NMNAT2. The NMNAT substrate NMN also appears to be pro-degenerative in both situations. Restricted outgrowth of NMNAT2-deficient axons is thus mechanistically related to the degeneration of established axons.
Axons require a constant supply of the labile axon survival factor Nmnat2 from their cell bodies to avoid spontaneous axon degeneration. Here we investigate the mechanism of fast axonal transport of ...Nmnat2 and its site of action for axon maintenance. Using dual-colour live-cell imaging of axonal transport in SCG primary culture neurons, we find that Nmnat2 is bidirectionally trafficked in axons together with markers of the trans-Golgi network and synaptic vesicles. In contrast, there is little co-migration with mitochondria, lysosomes, and active zone precursor vesicles. Residues encoded by the small, centrally located exon 6 are necessary and sufficient for stable membrane association and vesicular axonal transport of Nmnat2. Within this sequence, a double cysteine palmitoylation motif shared with GAP43 and surrounding basic residues are all required for efficient palmitoylation and stable association with axonal transport vesicles. Interestingly, however, disrupting this membrane association increases the ability of axonally localized Nmnat2 to preserve transected neurites in primary culture, while re-targeting the strongly protective cytosolic mutants back to membranes abolishes this increase. Larger deletions within the central domain including exon 6 further enhance Nmnat2 axon protective capacity to levels that exceed that of the slow Wallerian degeneration protein, Wld(S). The mechanism underlying the increase in axon protection appears to involve an increased half-life of the cytosolic forms, suggesting a role for palmitoylation and membrane attachment in Nmnat2 turnover. We conclude that Nmnat2 activity supports axon survival through a site of action distinct from Nmnat2 transport vesicles and that protein stability, a key determinant of axon protection, is enhanced by mutations that disrupt palmitoylation and dissociate Nmnat2 from these vesicles.
‘Dying back’ axon degeneration is a prominent feature of many age‐related neurodegenerative disorders and is widespread in normal ageing. Although the mechanisms of disease‐ and age‐related losses ...may differ, both contribute to symptoms. Here, we review recent advances in understanding axon pathology in age‐related neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. In particular, we highlight the importance of axonal transport, autophagy, traumatic brain injury and mitochondrial quality control. We then place these disease mechanisms in the context of changes to axons and dendrites that occur during normal ageing. We discuss what makes ageing such an important risk factor for many neurodegenerative disorders and conclude that the processes of normal ageing and disease combine at the molecular, cellular or systems levels in a range of disorders to produce symptoms. Pathology identical to disease also occurs at the cellular level in most elderly individuals. Thus, normal ageing and age‐related disease are inextricably linked and the term ‘healthy ageing’ downplays the important contributions of cellular pathology. For a full understanding of normal ageing or age‐related disease we must study both processes.
Systemic inflammation has been linked to synapse loss and cognitive decline in human patients and animal models. A role for microglial release of pro-inflammatory cytokines has been proposed based on ...in vivo and primary culture studies. However, mechanisms are hard to study in vivo as specific microglial ablation is challenging and the extracellular fluid cannot be sampled without invasive methods. Primary cultures have different limitations as the intricate multicellular architecture in the brain is not fully reproduced. It is essential to confirm proposed brain-specific mechanisms of inflammatory synapse loss directly in brain tissue. Organotypic hippocampal slice cultures (OHSCs) retain much of the in vivo neuronal architecture, synaptic connections and diversity of cell types whilst providing convenient access to manipulate and sample the culture medium and observe cellular reactions.
OHSCs were generated from P6-P9 C57BL/6 mice. Inflammation was induced via addition of lipopolysaccharide (LPS), and cultures were analysed for changes in synaptic proteins, gene expression and protein secretion. Microglia were selectively depleted using clodronate, and the effect of IL1β was assessed using a specific neutralising monoclonal antibody.
LPS treatment induced loss of the presynaptic protein synaptophysin without altering PSD95 or Aβ protein levels. Depletion of microglia prior to LPS application prevented the loss of synaptophysin, whilst microglia depletion after the inflammatory insult was partially effective, although less so than pre-emptive treatment, indicating a time-critical window in which microglia can induce synaptic damage. IL1β protein and mRNA were increased after LPS addition, with these effects also prevented by microglia depletion. Direct application of IL1β to OHSCs resulted in synaptophysin loss whilst pre-treatment with IL1β neutralising antibody prior to LPS addition prevented a significant loss of synaptophysin but may also impact basal synaptic levels.
The loss of synaptophysin in this system confirms LPS can act directly within brain tissue to disrupt synapses, and we show that microglia are the relevant cellular target when all major CNS cell types are present. By overcoming limitations of primary culture and in vivo work, our study strengthens the evidence for a key role of microglia-derived IL1β in synaptic dysfunction after inflammatory insult.
Summary Background Cancer survival is a key measure of the effectiveness of health-care systems. Persistent regional and international differences in survival represent many avoidable deaths. ...Differences in survival have prompted or guided cancer control strategies. This is the first study in a programme to investigate international survival disparities, with the aim of informing health policy to raise standards and reduce inequalities in survival. Methods Data from population-based cancer registries in 12 jurisdictions in six countries were provided for 2·4 million adults diagnosed with primary colorectal, lung, breast (women), or ovarian cancer during 1995–2007, with follow-up to Dec 31, 2007. Data quality control and analyses were done centrally with a common protocol, overseen by external experts. We estimated 1-year and 5-year relative survival, constructing 252 complete life tables to control for background mortality by age, sex, and calendar year. We report age-specific and age-standardised relative survival at 1 and 5 years, and 5-year survival conditional on survival to the first anniversary of diagnosis. We also examined incidence and mortality trends during 1985–2005. Findings Relative survival improved during 1995–2007 for all four cancers in all jurisdictions. Survival was persistently higher in Australia, Canada, and Sweden, intermediate in Norway, and lower in Denmark, England, Northern Ireland, and Wales, particularly in the first year after diagnosis and for patients aged 65 years and older. International differences narrowed at all ages for breast cancer, from about 9% to 5% at 1 year and from about 14% to 8% at 5 years, but less or not at all for the other cancers. For colorectal cancer, the international range narrowed only for patients aged 65 years and older, by 2–6% at 1 year and by 2–3% at 5 years. Interpretation Up-to-date survival trends show increases but persistent differences between countries. Trends in cancer incidence and mortality are broadly consistent with these trends in survival. Data quality and changes in classification are not likely explanations. The patterns are consistent with later diagnosis or differences in treatment, particularly in Denmark and the UK, and in patients aged 65 years and older. Funding Department of Health, England; and Cancer Research UK.
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