Transcriptome analysis reveals a strong positive correlation between human Schlafen family member 11 (SLFN11) expression and the sensitivity of tumor cells to DNA-damaging agents (DDAs). Here, we ...show that SLFN11 preferentially inhibits translation of the serine/threonine kinases ATR and ATM upon DDA treatment based on distinct codon usage without disrupting early DNA damage response signaling. Type II transfer RNAs (tRNAs), which include all serine and leucine tRNAs, are cleaved in a SLFN11-dependent manner in response to DDAs. Messenger RNAs encoded by genes with high TTA (Leu) codon usage, such as ATR, display utmost susceptibility to translational suppression by SLFN11. Specific attenuation of tRNA-Leu-TAA sufficed to ablate ATR protein expression and restore the DDA sensitivity of SLFN11-deficient cells. Our study uncovered a novel mechanism of codon-specific translational inhibition via SLFN11-dependent tRNA cleavage in the DNA damage response and supports the notion that SLFN11-deficient tumor cells can be resensitized to DDAs by targeting ATR or tRNA-Leu-TAA.
Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. As mitochondrial dysfunction critically contributes to the pathogenesis of MI, intensive research is focused on the ...development of therapeutic strategies targeting mitochondrial homeostasis. Mitochondria possess a quality control system which maintains and restores their structure and function by regulating mitochondrial fission, fusion, biogenesis, degradation and death. In response to slight damage such as transient hypoxia or mild oxidative stress, mitochondrial metabolism shifts from oxidative phosphorylation to glycolysis, in order to reduce oxygen consumption and maintain ATP output. Mitochondrial dynamics are also activated to modify mitochondrial shape and structure, in order to meet cardiomyocyte energy requirements through augmenting or reducing mitochondrial mass. When damaged mitochondria cannot be repaired, poorly structured mitochondria will be degraded through mitophagy, a process which is often accompanied by mitochondrial biogenesis. Once the insult is severe enough to induce lethal damage in the mitochondria and the cell, mitochondrial death pathway activation is an inevitable consequence, and the cardiomyocyte apoptosis or necrosis program will be initiated to remove damaged cells. Mitochondrial quality surveillance is a hierarchical system preserving mitochondrial function and defending cardiomyocytes against stress. A failure of this system has been regarded as one of the potential pathologies underlying MI. In this review, we discuss the recent findings focusing on the role of mitochondrial quality surveillance in MI, and highlight the available therapeutic approaches targeting mitochondrial quality surveillance during MI.
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DOBA, FSPLJ, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
Population ageing represents a global challenge for future end-of-life care. Given new trends in place of death, it is vital to examine where the rising number of deaths will occur in ...future years and implications for health and social care.
Aim:
To project where people will die from 2015 to 2040 across all care settings in England and Wales.
Design:
Population-based trend analysis and projections using simple linear modelling. Age- and gender-specific proportions of deaths in hospital, care home, home, hospice and ‘other’ were applied to numbers of expected future deaths.
Setting/population:
All deaths (2004–2014) from death registration data and predicted deaths (2015–2040) from official population forecasts in England and Wales.
Results:
Annual deaths are projected to increase from 501,424 in 2014 (38.8% aged 85 years and over) to 635,814 in 2040 (53.6% aged 85 years and over). Between 2004 and 2014, proportions of home and care home deaths increased (18.3%–22.9% and 16.7%– 21.2%) while hospital deaths declined (57.9%–48.1%). If current trends continue, numbers of deaths in care homes and homes will increase by 108.1% and 88.6%, with care home the most common place of death by 2040. If care home capacity does not expand and additional deaths occur in hospital, hospital deaths will start rising by 2023.
Conclusion:
To sustain current trends, end-of-life care provision in care homes and the community needs to double by 2040. An infrastructure across care settings that supports rising annual deaths is urgently needed; otherwise, hospital deaths will increase.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Adipose tissue inflammation and dysfunction are associated with obesity‐related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells ...accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug‐inducible “suicide” genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra‐abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity‐related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity‐related metabolic dysfunction and its complications.
Obesity induces the formation of senescent cells, which contribute to inflammation, insulin resistance, and organ dysfunction. Senescent cell clearance may be an effective strategy for alleviating important elements of obesity‐related metabolic dysfunction.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Summary
Objective
There is not yet a clear consensus on the incidence of sudden unexpected death in epilepsy (SUDEP) or the extent of its burden on public health. In this systematic review, we seek ...to summarize the incidence of SUDEP and its age distribution, as well as the years of potential life lost and cumulative risks of SUDEP for persons with epilepsy.
Methods
We conducted a systematic search for epidemiologic studies of sudden death in epilepsy and rated their quality of evidence. We pooled data from comparable higher quality population‐based studies of SUDEP incidence across all age groups, calculating the overall incidence of SUDEP per 100,000 population, and per 1,000 people with epilepsy. Using standard formulas, we also calculated the years of potential life lost and cumulative risks associated with SUDEP.
Results
SUDEP has an estimated overall crude annual incidence rate of 0.81 cases per 100,000 population, or 1.16 cases per 1,000 patients with epilepsy. Comparing years of potential life lost from SUDEP with selected other neurologic diseases, SUDEP ranks second only to stroke.
Significance
Despite limitations to the data on which our analysis is based, we conclude that the public health burden of SUDEP, which has previously been underappreciated, is substantial and deserves much more attention from clinicians, researchers, and the public health community.
A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Respiratory papillomas, caused by human papillomaviruses types 6 and 11 (HPV6/11), are premalignant lesions with potential for malignant conversion. The cytokine and chemokine micromilieu of ...papillomas is T(H)2-like with a marked absence of IFN-γ expression. To illuminate why patients with recurrent respiratory papillomatosis (RRP) fail to effectively control their disease, we further investigated the suppressive cellular microenvironment in papillomas.
CD4(+)CD25(+)CD127(low/-)Foxp3(+) regulatory T cells (Treg) and CD4(+)CD25(-)CD127(low/-)Foxp3(-) T cells within papillomas were characterized and isolated. Their suppressor function was measured by inhibition of peripheral blood mononuclear cell (PBMC) proliferation. Expression of PD-1, CD69, and Helios was identified on these T cells. PD-L1, PD-L2, CCL17, and CCL22 mRNA was also identified in papillomas by quantitative PCR.
Functional Tregs were markedly enriched in papillomas and strongly inhibited anti-CD3 and anti-CD28 antibody activated PBMC proliferation. The natural Treg marker Helios was reduced on Tregs from papillomas, indicating that the majority of Tregs in papillomas are adaptive. The majority of the papilloma-derived CD4(+) T cells expressed the CD4(+)CD25(-)CD127(low/-)Foxp3(-)PD1(+)CD69(+) phenotype and failed to suppress PBMC proliferation, suggesting that they are chronically activated and exhausted. The Treg-attracting chemokine CCL22 was equally expressed by all laryngeal tissues examined. However, CCL17 was robustly expressed by papillomas compared with unaffected laryngeal tissues from RRP patients and individuals without RRP. PD-L1 was elevated in papillomas compared with control laryngeal tissues.
Papilloma CD4(+) T cells are enriched with functional Tregs, and the adaptive Helios(-) Treg fraction was increased within the T(H)2-like papilloma micromilieu. CD4(+)CD25(-)CD127(low/-)Foxp3(-) T-cells failed to suppress PBMC proliferation and may be exhausted. The PD-1/PDL-1 pathway may represent an additional immunosuppressive mechanism that contributes to defective HPV6/11 clearance in RRP.
Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed ...cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.
Stroke recently declined from the third to the fourth leading cause of death in the United States, its first rank transition among sources of American mortality in nearly 75 years.
This is a ...narrative review supplemented by new analyses of Centers for Disease Control and Prevention National Vital Statistics Reports from 1931 to 2008.
Historically, stroke transitioned from the second to the third leading cause of death in the United States in 1937, but stroke death rates were essentially stable from 1930 to 1960. Then a long, great decline began, moderate in the 1960s, precipitous in the 1970s and 1980s, and moderate again in the 1990s and 2000s. By 2008, age-adjusted annual death rates from stroke were three fourths less than the historic 1931 to 1960 norm (40.6 versus 175.0 per 100,000). Total actual stroke deaths in the United States declined from a high of 214,000 in 1973 to 134,000 in 2008. Improved stroke prevention, through control of hypertension, hyperlipidemia, and tobacco, contributed most greatly to the mortality decline with a lesser but still substantial contribution of improved acute stroke care. Persisting challenges include race-ethnicity, sex, and geographic disparities in stroke mortality; the burden of stroke disability; the expanding obesity epidemic and aging of the US population; and the epidemic of cerebrovascular disease in low- and middle-income countries worldwide.
The recent rank decline of stroke among leading causes of American death is testament to a half century of societal progress in cerebrovascular disease prevention and acute care. Renewed commitments are needed to preserve and broaden this historic achievement.
Background Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on ...tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. Objective We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. Methods We performed multiparametric cytofluorimetric analysis of PD-1+ NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. Results We provide unequivocal evidence that PD-1 is highly expressed (PD-1bright ) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56dim but not CD56bright NK cells and is confined to fully mature NK cells characterized by the NKG2A− KIR+ CD57+ phenotype. Proportions of PD-1bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their possible induction/expansion in tumor environments. Functional analysis revealed a reduced proliferative capability in response to cytokines, low degranulation, and impaired cytokine production on interaction with tumor targets. Conclusions We have identified and characterized a novel subpopulation of human NK cells expressing high levels of PD-1. These cells have the phenotypic characteristics of fully mature NK cells and are increased in patients with ovarian carcinoma. They display low proliferative responses and impaired antitumor activity that can be partially restored by antibody-mediated disruption of PD-1/programmed death ligand interaction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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