Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper ...induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.
Checkpoints inhibitors anti-programmed death 1 (PD1) and anti-programmed death ligand 1 (PD-L1) restore immunity against tumour. By their mechanism of action, they could induce immune-related adverse ...events (irAEs) that can theoretically involve all organs. These irAEs, especially those that are rare, remain incompletely described. Immune-related eosinophilia has been described with ipilimumab and was interestingly associated with favourable response to immunotherapy. We report here the first series of patients who experienced immune-related eosinophilia due to anti-PDI or anti-PD-L1 antibodies. Immune-related eosinophilia is a new biological immune-related adverse effect with anti-PD-1 or anti-PD-Ll. To the best of our knowledge, we report here the first case series of immune-related eosinophilia with anti-PDl or anti-PD-Ll. Importantly, we show that kinetics of leukocyte changes was restricted to the eosinophil lineage. This immune-related eosinophilia was rare (estimated frequency of 2.9%), began at 3.0 months with a peak achieved at 6.4 months. Patients with immune-related eosinophilia remain asymptomatic. Larger prospective studies are required to search for a link with favourable anti-tumour response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The Precambrian explosion led to the rapid appearance of most major animal phyla alive today. It has been argued that the complexity of life has steadily increased since that event. Here we challenge ...this hypothesis through the characterization of apoptosis in reef-building corals, representatives of some of the earliest animals. Bioinformatic analysis reveals that all of the major components of the death receptor pathway are present in coral with high-predicted structural conservation with Homo sapiens . The TNF receptor-ligand superfamilies (TNFRSF/TNFSF) are central mediators of the death receptor pathway, and the predicted proteome of Acropora digitifera contains more putative coral TNFRSF members than any organism described thus far, including humans. This high abundance of TNFRSF members, as well as the predicted structural conservation of other death receptor signaling proteins, led us to wonder what would happen if corals were exposed to a member of the human TNFSF (HuTNFα). HuTNFα was found to bind directly to coral cells, increase caspase activity, cause apoptotic blebbing and cell death, and finally induce coral bleaching. Next, immortalized human T cells (Jurkats) expressing a functional death receptor pathway (WT) and a corresponding Fas-associated death domain protein (FADD) KO cell line were exposed to a coral TNFSF member (AdTNF1) identified and purified here. AdTNF1 treatment resulted in significantly higher cell death (P < 0.0001) in WT Jurkats compared with the corresponding FADD KO, demonstrating that coral AdTNF1 activates the H. sapiens death receptor pathway. Taken together, these data show remarkable conservation of the TNF-induced apoptotic response representing 550 My of functional conservation.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Cardiovascular remodelling in the conditioned athlete is frequently associated with physiological ECG changes. Abnormalities, however, may be detected which represent expression of an underlying ...heart disease that puts the athlete at risk of arrhythmic cardiac arrest during sports. It is mandatory that ECG changes resulting from intensive physical training are distinguished from abnormalities which reflect a potential cardiac pathology. The present article represents the consensus statement of an international panel of cardiologists and sports medical physicians with expertise in the fields of electrocardiography, imaging, inherited cardiovascular disease, cardiovascular pathology, and management of young competitive athletes. The document provides cardiologists and sports medical physicians with a modern approach to correct interpretation of 12-lead ECG in the athlete and emerging understanding of incomplete penetrance of inherited cardiovascular disease. When the ECG of an athlete is examined, the main objective is to distinguish between physiological patterns that should cause no alarm and those that require action and/or additional testing to exclude (or confirm) the suspicion of an underlying cardiovascular condition carrying the risk of sudden death during sports. The aim of the present position paper is to provide a framework for this distinction. For every ECG abnormality, the document focuses on the ensuing clinical work-up required for differential diagnosis and clinical assessment. When appropriate the referral options for risk stratification and cardiovascular management of the athlete are briefly addressed.
Objective
To assess the strength of the evidence indicative of prostate cancer (PCa) progression as the adjudicated cause of death, according to age at death and PCa risk category.
Patients and ...Methods
Using data from the Prostate Cancer data Base Sweden, we identified a study frame of 5543 men with PCa registered as the cause of death according to the Cause of Death Register. We assessed the evidence of PCa progression through a review of healthcare records for a stratified sample of 495/5543. We extracted data on prostate‐specific antigen levels, presence of metastases on imaging, and PCa treatments, and quantified the evidence of disease progression using a points system.
Results
Both no evidence and moderate evidence for PCa progression was more common in men aged >85 years at death than those aged <85 years (29% vs 14%). Among the latter, the proportion with no evidence or moderate evidence for PCa progression was 21% for low‐risk, 14% for intermediate‐risk, 8% for high‐risk, and 0% for metastatic PCa. In contrast, in men aged >85 years, there was little difference in the proportion with no evidence or moderate evidence of PCa progression between PCa risk categories; 31% for low‐risk, 29% for intermediate‐risk, 29% for high‐risk, and 21% for metastatic PCa. Of the 5543 men who died from PCa, 13% (95% confidence interval 5–19%) were estimated to have either no evidence or moderate evidence of PCa progression.
Conclusions
Weak evidence for PCa progression as cause of death was more common in older men with PCa and in those with low‐risk PCa. This has implications for interpretation of mortality statistics especially when assessing screening and early treatment of PCa because the beneficial effect of earlier diagnosis could be masked by erroneous adjudication of PCa as cause of death in older men, particular those with localised disease at diagnosis.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
This study characterized 3- to 6-year-old children's understanding of death as a function of depression status, suicidal ideation (SI), and media consumption.
Participants were 79 children with ...depression (3.0-6.11 years old) who completed a comprehensive psychiatric assessment and experimenter-led death interview and a comparison group of 60 healthy children (4.0-7.12 years old). The interview assessed children's understanding of 5 concepts of death: universality, applicability, irreversibility, cessation, and causality. Children's mastery of each concept and overall understanding of death was examined as a function of depression and SI status: depressed with SI (n = 22), depressed without SI (n = 57), and healthy (n = 60). Children's observed emotional reactions to hearing about natural death, accidental death, and suicide were assessed by death-themed stories. Parent reports of children's television and videogames/internet consumption assessed links between media exposure and understanding of death.
Children with depression and SI scored higher on overall understanding of death than those with depression without SI and healthy children. They also exhibited more sad and anxious affect listening to death-themed stories and were more likely to describe death as caused by violence. Across this sample, older children also were more likely to depict death as violent. More television use was associated with less understanding of death, including the concept of irreversibility.
Children with depression and SI have a more advanced understanding of death than their peers, dispelling the myth that these ideations arise in the context of a poor understanding of death. The increase in violence attributions across early childhood could indicate increasing normalization of violence in children's perceptions of death.
A Randomized Controlled Trial of PCIT-ED for Preschool Depression; http://clinicaltrials.gov; NCT00595283.
TP53INP2 positively regulates autophagy by binding to Atg8 proteins. Here, we uncover a novel role of TP53INP2 in death‐receptor signaling. TP53INP2 sensitizes cells to apoptosis induced by death ...receptor ligands. In keeping with this, TP53INP2 deficiency in cultured cells or mouse livers protects against death receptor‐induced apoptosis. TP53INP2 binds caspase‐8 and the ubiquitin ligase TRAF6, thereby promoting the ubiquitination and activation of caspase‐8 by TRAF6. We have defined a TRAF6‐interacting motif (TIM) and a ubiquitin‐interacting motif in TP53INP2, enabling it to function as a scaffold bridging already ubiquitinated caspase‐8 to TRAF6 for further polyubiquitination of caspase‐8. Mutations of key TIM residues in TP53INP2 abrogate its interaction with TRAF6 and caspase‐8, and subsequently reduce levels of death receptor‐induced apoptosis. A screen of cancer cell lines showed that those with higher protein levels of TP53INP2 are more prone to TRAIL‐induced apoptosis, making TP53INP2 a potential predictive marker of cancer cell responsiveness to TRAIL treatment. These findings uncover a novel mechanism for the regulation of caspase‐8 ubiquitination and reveal TP53INP2 as an important regulator of the death receptor pathway.
Synopsis
Death cell receptors initiate apoptosis, necroptosis or inflammation depending on their cell‐surface expression, ligand concentration and intracellular context. The autophagy regulator TP53INP2 promotes death receptor‐induced apoptosis through TRAF6‐dependent ubiquitination of caspase‐8.
TP53INP2 sensitizes cancer cells to death receptor‐induced apoptosis.
Knockout of TP53INP2 protects cultured cells and mouse livers from FasL‐induced apoptosis.
TP53INP2 binds TRAF6 E3 ligase and ubiquitinated caspase‐8 via its TRAF6‐ and ubiquitin‐interacting motifs, respectively, to enhance caspase‐8 poly‐ubiquitination.
High TP53INP2 levels may predict responsiveness of cancer cells to TRAIL treatment.
The autophagy regulator TP53INP2 promotes death receptor‐induced apoptosis through TRAF6‐dependent ubiquitination of caspase‐8.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
As mortality rates decline, life expectancy increases, and populations age, non-fatal outcomes of diseases and injuries are becoming a larger component of the global burden of disease. The Global ...Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016.
We estimated prevalence and incidence for 328 diseases and injuries and 2982 sequelae, their non-fatal consequences. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between incidence, prevalence, remission, and cause of death rates for each condition. For some causes, we used alternative modelling strategies if incidence or prevalence needed to be derived from other data. YLDs were estimated as the product of prevalence and a disability weight for all mutually exclusive sequelae, corrected for comorbidity and aggregated to cause level. We updated the Socio-demographic Index (SDI), a summary indicator of income per capita, years of schooling, and total fertility rate. GBD 2016 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).
Globally, low back pain, migraine, age-related and other hearing loss, iron-deficiency anaemia, and major depressive disorder were the five leading causes of YLDs in 2016, contributing 57·6 million (95% uncertainty interval UI 40·8–75·9 million 7·2%, 6·0–8·3), 45·1 million (29·0–62·8 million 5·6%, 4·0–7·2), 36·3 million (25·3–50·9 million 4·5%, 3·8–5·3), 34·7 million (23·0–49·6 million 4·3%, 3·5–5·2), and 34·1 million (23·5–46·0 million 4·2%, 3·2–5·3) of total YLDs, respectively. Age-standardised rates of YLDs for all causes combined decreased between 1990 and 2016 by 2·7% (95% UI 2·3–3·1). Despite mostly stagnant age-standardised rates, the absolute number of YLDs from non-communicable diseases has been growing rapidly across all SDI quintiles, partly because of population growth, but also the ageing of populations. The largest absolute increases in total numbers of YLDs globally were between the ages of 40 and 69 years. Age-standardised YLD rates for all conditions combined were 10·4% (95% UI 9·0–11·8) higher in women than in men. Iron-deficiency anaemia, migraine, Alzheimer's disease and other dementias, major depressive disorder, anxiety, and all musculoskeletal disorders apart from gout were the main conditions contributing to higher YLD rates in women. Men had higher age-standardised rates of substance use disorders, diabetes, cardiovascular diseases, cancers, and all injuries apart from sexual violence. Globally, we noted much less geographical variation in disability than has been documented for premature mortality. In 2016, there was a less than two times difference in age-standardised YLD rates for all causes between the location with the lowest rate (China, 9201 YLDs per 100 000, 95% UI 6862–11943) and highest rate (Yemen, 14 774 YLDs per 100 000, 11 018–19 228).
The decrease in death rates since 1990 for most causes has not been matched by a similar decline in age-standardised YLD rates. For many large causes, YLD rates have either been stagnant or have increased for some causes, such as diabetes. As populations are ageing, and the prevalence of disabling disease generally increases steeply with age, health systems will face increasing demand for services that are generally costlier than the interventions that have led to declines in mortality in childhood or for the major causes of mortality in adults. Up-to-date information about the trends of disease and how this varies between countries is essential to plan for an adequate health-system response.
Bill & Melinda Gates Foundation, and the National Institute on Aging and the National Institute of Mental Health of the National Institutes of Health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Initially described as an adaptor molecule for death receptor (DR)-mediated apoptosis, Fas-associated death domain (FADD) was later implicated in nonapoptotic cellular processes. During the last ...decade, FADD has been shown to participate and regulate most of the signalosome complexes, including necrosome, FADDosome, innateosome, and inflammasome. Given the role of these signaling complexes, FADD has emerged as a new actor in innate immunity, inflammation, and cancer development. Concomitant to these new roles, a surprising number of mechanisms deemed to regulate FADD functions have been identified, including post-translational modifications of FADD protein and FADD secretion. This review focuses on recent knowledge of the biological roles of FADD, a pleiotropic molecule having multiple partners, and its impact in cancer, innate immunity, and inflammation.
FADD is part of most signalosome complexes including the necroptosome, FADDosome, innateosome and inflammasome.
Human FADD gene can be a potential driver in cancer through its amplification, which has been associated with both metastasis and poor overall survival for certain malignancies.
FADD has been implicated in immune defenses against bacterial and viral infections, and a human FADD missense mutation has led to severe and potentially lethal, infectious diseases.
FADD activity can be modulated by several post-translational modifications (phosphorylation, SUMOylation, ubiquitination, cleavage, and arginine GlcNAcylation) as well as via its cellular localization (nuclear/cytoplasmic/extracellular).
FADD might play a critical role in cancer, innate immunity, and inflammation. The role of FADD in tumoral and inflammatory responses may be dual, with FADD exerting either anti- or protumoral/inflammatory effects, depending the cell type and model.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer associated with advanced age and immunosuppression. Over the past decade, an association has been discovered between MCC and either ...integration of the Merkel cell polyomavirus, which likely drives tumorigenesis, or somatic mutations owing to ultraviolet-induced DNA damage. Both virus-positive and virus-negative MCCs are immunogenic, and inhibition of the programmed cell death protein 1 (PD-1)-programmed cell death 1 ligand 1 (PD-L1) immune checkpoint has proved to be highly effective in treating patients with metastatic MCC; however, not all patients have a durable response to immunotherapy. Despite these rapid advances in the understanding and management of patients with MCC, many basic, translational and clinical research questions remain unanswered. In March 2018, an International Workshop on Merkel Cell Carcinoma Research was held at the US National Cancer Institute, at which academic, government and industry experts met to identify the highest-priority research questions. Here, we review the biology and treatment of MCC and report the consensus-based recommendations agreed upon during the workshop.
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NUK, OILJ, SBMB, UL, UM, UPUK
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