Necroptosis in the Pathophysiology of Disease Khoury, Mitri K.; Gupta, Kartik; Franco, Sarah R. ...
The American journal of pathology,
February 2020, 2020-02-00, 20200201, Letnik:
190, Številka:
2
Journal Article
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Over the past 15 years, elegant studies have demonstrated that in certain conditions, programed cell death resembles necrosis and depends on a unique molecular pathway with no overlap with apoptosis. ...This form of regulated necrosis is represented by necroptosis, in which the receptor-interacting protein kinase-3 and its substrate mixed-lineage kinase domain-like protein play a crucial role. With the development of knockout mouse models and molecular inhibitors unique to necroptotic proteins, this cell death has been found to occur in virtually all tissues and diseases evaluated. There are different immunologic consequences depending on whether cells die through apoptosis or necroptosis. Therefore, distinguishing between these two forms of cell death may be crucial during pathologic evaluations. In this review, we provide an understanding of necroptotic cell-death and highlight diseases in which necroptosis has been found to play a role. We also discuss the inhibitors of necroptosis and the ways these inhibitors have been used in preclinical models of diseases. These two discussions offer an understanding of the role of necroptosis in diseases and will foster efforts to pharmacologically target this unique yet pervasive form of programed cell death in the clinic.
Tumors are complex cellular and acellular environments within which cancer clones are under continuous selection pressures. Cancer cells are in a permanent mode of interaction and competition with ...each other as well as with the immediate microenvironment. In the course of these competitive interactions, cells share information regarding their general state of fitness, with less‐fit cells being typically eliminated via apoptosis at the hands of those cells with greater cellular fitness. Competitive interactions involving exchange of cell fitness information have implications for tumor growth, metastasis, and therapy outcomes. Recent research has highlighted sophisticated pathways such as Flower, Hippo, Myc, and p53 signaling, which are employed by cancer cells and the surrounding microenvironment cells to achieve their evolutionary goals by means of cell competition mechanisms. In this review, we discuss these recent findings and explain their importance and role in evolution, growth, and treatment of cancer. We further consider potential physiological conditions, such as hypoxia and chemotherapy, that can function as selective pressures under which cell competition mechanisms may evolve differently or synergistically to confer oncogenic advantages to cancer.
In this review, Rajan Gogna and colleagues integrate developmental and cancer perspectives on the role of cell competition mechanisms as drivers of malignancies at tissue level.
The efficacy, safety, and clinical importance of extended-duration thromboprophylaxis (EDT) for prevention of venous thromboembolism (VTE) in medical patients remain unclear. We compared the efficacy ...and safety of EDT in patients hospitalized for medical illness.
Electronic databases of PubMed/MEDLINE, EMBASE, Cochrane Central, and ClinicalTrials.gov were searched from inception to March 21, 2019. We included randomized clinical trials (RCTs) reporting use of EDT for prevention of VTE. We performed trial sequential and cumulative meta-analyses to evaluate EDT effects on the primary efficacy endpoint of symptomatic VTE or VTE-related death, International Society on Thrombosis and Haemostasis (ISTH) major or fatal bleeding, and all-cause mortality. The pooled number needed to treat (NNT) to prevent one symptomatic or fatal VTE event and the number needed to harm (NNH) to cause one major or fatal bleeding event were calculated. Across 5 RCTs with 40,247 patients (mean age: 67-77 years, proportion of women: 48%-54%, most common reason for admission: heart failure), the duration of EDT ranged from 24-47 days. EDT reduced symptomatic VTE or VTE-related death compared with standard of care (0.8% versus 1.2%; risk ratio RR: 0.61, 95% confidence interval CI: 0.44-0.83; p = 0.002). EDT increased risk of ISTH major or fatal bleeding (0.6% versus 0.3%; RR: 2.04, 95% CI: 1.42-2.91; p < 0.001) in both meta-analyses and trial sequential analyses. Pooled NNT to prevent one symptomatic VTE or VTE-related death was 250 (95% CI: 167-500), whereas NNH to cause one major or fatal bleeding event was 333 (95% CI: 200-1,000). Limitations of the study include variation in enrollment criteria, individual therapies, duration of EDT, and VTE detection protocols across included trials.
In this systematic review and meta-analysis of 5 randomized trials, we observed that use of a post-hospital discharge EDT strategy for a 4-to-6-week period reduced symptomatic or fatal VTE events at the expense of increased risk of major or fatal bleeding. Further investigations are still required to define the risks and benefits in discrete medically ill cohorts, evaluate cost-effectiveness, and develop pathways for targeted implementation of this postdischarge EDT strategy.
PROSPERO CRD42018109151.
Receptor-interacting protein kinase 3 executes a form of regulated necrosis called necroptosis. Upon induction of an altered conformation by chemical inhibitors or via mutations in its kinase site, ...RIPK3 associates with a multiprotein complex called the ripoptosome—a signaling platform containing FADD, RIPK1, caspase 8, and cFLIP—and becomes decisive in the execution of apoptosis. Surprisingly, in contexts not completely understood, the ripoptosome itself cleaves RIPK3, highlighting an apparent conundrum on how RIPK3 fulfills its role via the complex responsible for its own degradation. Recently, ripoptosome assembly was found to occur in mitosis where we found elevated RIPK3 levels. We now report that PLK1 directly associates with RIPK3 and phosphorylates it at S369 as cells enter mitosis. G2/M phase RIPK3 has pro-apoptotic activity but upon release from ripoptosome, can trigger necroptosis. Taken together, phosphorylation of RIPK3 at S369 prevents its ripoptosome-mediated cleavage thereby retaining its pro-death activity during mitosis.
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•Inhibiting RIPK3, a necroptotic kinase, triggers apoptosis via the ripoptosome•Ripoptosome normally cleaves RIPK3 and is assembled in mitosis•pS369 in G2/M phases prevents RIPK3 proteolysis via ripoptosome•Phosphorylation of S369 by PLK1 enables cell death plasticity in G2/M phases
Biological Sciences; Cell Biology; Functional Aspects of Cell Biology
In the contemporary energy landscape, power generation comprises a blend of renewable and non-renewable resources, with the major supply of electrical energy fulfilled by non-renewable sources, ...including coal and gas, among others. Renewable energy resources are challenged by their dependency on unpredictable weather conditions. For instance, solar energy hinges on clear skies, and wind energy relies on consistent and sufficient wind flow. However, as a consequence of the finite supply and detrimental environmental impact associated with non-renewable energy sources, it is required to reduce dependence on such non-renewable sources. This can be achieved by precisely predicting the generation of renewable energy using a data-driven approach. The prediction accuracy for electric load plays a very significant role in this system. If we have an appropriate estimate of residential and commercial load, then a strategy could be defined for the efficient supply to them by renewable and non-renewable energy sources through a smart grid, which analyzes the demand-supply and devises the supply mechanism accordingly. Predicting all such components, i.e., power generation and load forecasting, involves a data-driven approach where sensitive data (such as user electricity consumption patterns and weather data near power generation setups) is used for model training, raising the issue of data privacy and security concerns. Hence, the work proposes Federated Smart Grid (FedGrid), a secure framework that would be able to predict the generation of renewable energy and forecast electric load in a privacy-oriented approach through federated learning. The framework collectively analyzes all such predictive models for efficient electric supply.
Purpose of Review
South Asia has around 1/6
th
of the current global population. Epidemiological studies suggest that South Asians living in South Asia and diaspora are at an increased risk of ...premature atherosclerotic cardiovascular diseases (ASCVDs). This is due to an interplay of genetic, acquired, and environmental risk factors. Due to its increasing share of the global population, clinicians need to know the reasons for this early predisposition, and strategies for early identification and mitigation.
Recent Findings
South Asians have earlier onset of cardiometabolic risk factors such as insulin resistance, hypertension, and central adiposity. This increased risk is seen in both native South Asians and the diaspora.
Summary
South Asians have earlier onset of ASCVD due to an earlier onset of cardiometabolic risk factors. Health promotion and early identification of these risk factors are essential to mitigate this ongoing crisis.
Ventricular premature contractions (VPCs) are a common finding during cardiac stress tests. The independent prognostic value of these findings in patients in asymptomatic patients is unclear.
We ...conducted a systematic review and meta-analysis of observational studies exploring the independent prognostic value of VPCs to predict all-cause mortality. The secondary outcome was cardiovascular (CV) mortality. We excluded studies that did not report outcomes after adjusting for ≥1 confounder. Random effect meta-analyses were used to predict cumulative hazard ratios. We stratified results based on VPC during exercise or recovery.
We found 7 studies with 24,518 patients that met our inclusion criteria. Two studies reported all-cause mortality only, 1 study reported CV mortality only, rest 4 reported both. There was significant heterogeneity in the baseline population, definition of high-risk VPCs, and variables used in adjusted models. Using multivariable summary estimates from individual studies, only VPCs during exercise were associated with a higher risk of all-cause mortality (HR 1.27, 95 % CI 1.07, 1.48). Both VPCs during exercise and recovery were associated with a higher risk CV mortality (HR 1.69, 95 % CI 1.19, 2.20, I
= 17.6 % and 1.62, 95 % CI 1.25, 2.00, p < 0.001 for both).
High-risk VPCs during exercise is associated with increased risk of all-cause and CV mortality, while those during recovery are associated with an increased risk of CV mortality only.
According to World Health Organization (WHO) guidelines, which have also been adopted by the National AIDS Control Organization (NACO), India, Efavirenz-based Anti-Retroviral Therapy (ART) is better ...in Human-Immunodeficiency-Virus (HIV)-infected patients who are also being treated with Rifampicin-based Anti-Tuberculous Therapy (ATT). However, Efavirenz is much more expensive. We hypothesize that Nevirapine is a cheaper alternative that possesses equal efficacy as Efavirenz in HIV-Tuberculosis (TB) co-infected patients.
A parallel open-label randomized clinical trial was conducted at All India Institute of Medical Sciences (AIIMS), New Delhi and National AIDS Research Institute (NARI), Pune. Those who were ART-naïve and co-infected with TB were randomized to receive either Nevirapine (Group 1)- or Efavirenz (Group 2)-based ART along with Rifampicin-based ATT. ATT was begun first in ART-naïve patients according to the NACO guidelines, with a median of 27 days between ATT and ART in both groups. The primary endpoint was a composite unfavourable outcome (death and/or ART failure) at 96 weeks, and the secondary outcome was successful TB treatment at 48 weeks.
A total of 284 patients (mean age 36.7 ± 8.1 years) were randomized in a 1:1 ratio to receive either Nevirapine (n = 144)- or Efavirenz (n = 140)-based ART after a median ATT-ART gap of 27 days. The median CD4 count was 105 cells/μl, with a median viral load of 820,200 copies/μl and no significant difference between the groups. Composite unfavourable outcomes were reported in 49 patients in the Nevirapine group and 51 patients in the Efavirenz group (35.3% vs. 36.9%; hazard ratio, 0.95, 95% confidence interval (CI), 0.63,1.43, adjusted). There was no difference in successful TB treatment outcome between the groups (71.5% vs. 65.6%, 95% CI -3.8,17.9, adjusted). The results were similar, showing no difference between the groups in the two centres of the study after adjusting for disease stage.
Composite unfavourable outcome in HIV-TB co-infected patients who were ART-naïve showed no statistically significant difference in the Nevirapine or Efavirenz groups.. Therefore, Nevirapine-based ART is a reasonable alternative to Efavirenz in resource-limited settings. However, multi-centric studies with larger sample sizes are required to confirm these findings.
NCT01805258 (Retrospectively registered on March 6, 2013) Date of registration: March 2013.
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