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Over the past 50 years, few therapeutic advances have been made in treating acute myeloid leukemia (AML), an aggressive form of blood cancer, despite vast improvements in our ability to classify the disease. Emerging evidence suggests the immune system is important in controlling AML progression and in determining prognosis. Natural killer (NK) cells are important cytotoxic effector cells of the innate lymphoid cell (ILC) family that have been shown to have potent anti-leukemic functions. Recent studies are now revealing impairment or dysregulation of other ILCs in various types of cancers, including AML, which limits the effectiveness of NK cells in controlling cancer progression. NK cell development and function are inhibited in AML patients, which results in worse clinical outcomes; however, the specific roles of other ILC populations in AML are just now beginning to be unraveled. In this review, we summarize what is known about the role of ILC populations in AML.

To assess survival patterns and predictors of mortality among patients admitted with COVID-19 to treatment centers in the Oromia region of Ethiopia from April 1 to August 31, 2021. A prospective cohort study design was employed, taking a sample of 854 patients selected from eight treatment centers in the region. The follow-up duration was the time interval from admission to the treatment center until the final disposition of patients at discharge (death, recovery, or failed to recover). Data were collected by computer tablet with an interviewer-administered questionnaire and checklist designed using CSPro 7.5 and exported to Stata 13 for analysis. Descriptive analysis was used to explore the characteristics of patients. The mortality rate was estimated by number of deaths per 1,000 person-days of observation. The survival duration was estimated by medians with IQR. The Kaplan-Meier method was used to compare the survival experiences of patients. To identify the predictors of time to death after hospitalization, a Cox proportional-hazard model was used. The magnitude of association was estimated using HRs with 95% CIs, and statistical significance was set at <0.05. The mortality rate among hospitalized patients was 9.9 per 1,000 person-days of observation and the median survival time after admission was 9 (IQR 9-10) days. Higher hazard of death was observed among patients who drank alcohol (AHR 2.0, 95% CI 1.2-3.3), required anticoagulants (AHR 10, 95% CI 1.2-91.5), glucocorticoids (AHR 1.7, 95% CI 1.1-2.8), and oxygen (AHR 4.7, 95% CI 1.1-22.0), those with acute respiratory distress syndrome (AHR 2.9, 95% CI 1.7-5.1), and critical patients admitted to intensive care units (AHR 3.4, 95% CI 2.0-5.9). The hazard of death is significantly predicted by alcohol use, requiring anticoagulants, glucocorticoids, or oxygen medication, acute respiratory distress syndrome complication, and being critical when admitted to intensive care units.

Aryl hydrocarbon receptor (AhR) is a transcription factor, which can be activated by a plethora of structure-diverse ligands. Historically, AhR is known for its involvements in regulation of metabolism of xenobiotics. However, normal physiological roles of AhR have been defined in other essential biological processes, including vascular growth and function, reproduction, and immunoresponses. In contrast, aberrant expression and activation of the AhR signaling pathway occur in a variety of human diseases, many of which (e.g., preeclampsia, atherosclerosis, and hypertension) could be associated with endothelial dysfunction. Indeed, emerging evidence has shown that either exogenous or endogenous AhR ligands can induce endothelial dysfunction in either an AhR-dependent or AhR-independent manner, possibly reliant on the blood vessel origin (artery and vein) of endothelial cells. Given that the AhR signaling pathway has broad impacts on endothelial and cardiovascular function, AhR ligands, AhR, and their downstream genes could be considered novel therapeutic targets for those endothelial-related diseases. This review will discuss the current knowledge of AhR's mediation on endothelial function and potential mechanisms underlying these actions with a focus on placental endothelial cells. Summary Sentence Aryl hydrocarbon receptor critically mediates endothelial function. Graphical Abstract

We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction is critical to the design of AHR-targeted cancer therapeutics. Molecular (siRNA, shRNA, AHR repressor, CRISPR-Cas9) and pharmacological (AHR inhibitors) approaches were used to confirm the hypothesis that AHR inhibition reduces human cancer cell invasion (irregular colony growth in 3D Matrigel cultures and Boyden chambers), migration (scratch wound assay) and metastasis (human cancer cell xenografts in zebrafish). Furthermore, these assays were used for a head-to-head comparison between AHR antagonists and agonists. AHR inhibition or knockdown/knockout consistently reduced human ER−/PR−/Her2− and inflammatory breast cancer cell invasion, migration, and metastasis. This was associated with a decrease in invasion-associated genes (e.g., Fibronectin, VCAM1, Thrombospondin, MMP1) and an increase in CDH1/E-cadherin, previously associated with decreased tumor aggression. Paradoxically, AHR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin and/or 3,3′-diindolylmethane) similarly inhibited irregular colony formation in Matrigel and blocked metastasis in vivo but accelerated migration. These data demonstrate the complexity of modulating AHR activity in cancer while suggesting that AHR inhibitors, and, under some circumstances, AHR agonists, may be useful as cancer therapeutics.

Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a classical exogenous synthetic ligand of AHR that has significant immunotoxic effects. Activation of AHR has beneficial effects on intestinal immune responses, but inactivation or overactivation of AHR can lead to intestinal immune dysregulation and even intestinal diseases. Sustained potent activation of AHR by TCDD results in impairment of the intestinal epithelial barrier. However, currently, AHR research has been more focused on elucidating physiologic AHR function than on dioxin toxicity. The appropriate level of AHR activation plays a role in maintaining gut health and protecting against intestinal inflammation. Therefore, AHR offers a crucial target to modulate intestinal immunity and inflammation. Herein, we summarize our current understanding of the relationship between AHR and intestinal immunity, the ways in which AHR affects intestinal immunity and inflammation, the effects of AHR activity on intestinal immunity and inflammation, and the effect of dietary habits on intestinal health through AHR. Finally, we discuss the therapeutic role of AHR in maintaining gut homeostasis and relieving inflammation. Graphical Abstract

In July 2021 extreme rainfall across Western Europe caused severe flooding and substantial impacts, including over 200 fatalities and extensive infrastructure damage within Germany and the Benelux countries. After the event, a hydrological assessment and a probabilistic event attribution analysis of rainfall data were initiated and complemented by discussing the vulnerability and exposure context. The global mean surface temperature (GMST) served as a covariate in a generalised extreme value distribution fitted to observational and model data, exploiting the dependence on GMST to estimate how anthropogenic climate change affects the likelihood and severity of extreme events. Rainfall accumulations in Ahr/Erft and the Belgian Meuse catchment vastly exceeded previous observed records. In regions of that limited size the robust estimation of return values and the detection and attribution of rainfall trends are challenging. However, for the larger Western European region it was found that, under current climate conditions, on average one rainfall event of this magnitude can be expected every 400 years at any given location. Consequently, within the entire region, events of similar magnitude are expected to occur more frequently than once in 400 years. Anthropogenic climate change has already increased the intensity of the maximum 1-day rainfall event in the summer season by 3–19 %. The likelihood of such an event to occur today compared to a 1.2 ∘C cooler climate has increased by a factor of 1.2–9. Models indicate that intensity and frequency of such events will further increase with future global warming. While attribution of small-scale events remains challenging, this study shows that there is a robust increase in the likelihood and severity of rainfall events such as the ones causing extreme impacts in July 2021 when considering a larger region.

Aryl hydrocarbon receptor (AHR) is an important regulator of skin barrier function. It also controls immune-mediated skin responses. The AHR modulates various physiological functions by acting as a sensor that mediates environment–cell interactions, particularly during immune and inflammatory responses. Diverse experimental systems have been used to assess the AHR’s role in skin inflammation, including in vitro assays of keratinocyte stimulation and murine models of psoriasis and atopic dermatitis. Similar approaches have addressed the role of AHR ligands, e.g., TCDD, FICZ, and microbiota-derived metabolites, in skin homeostasis and pathology. Tapinarof is a novel AHR-modulating agent that inhibits skin inflammation and enhances skin barrier function. The topical application of tapinarof is being evaluated in clinical trials to treat psoriasis and atopic dermatitis. In the present review, we summarize the effects of natural and synthetic AHR ligands in keratinocytes and inflammatory cells, and their relevance in normal skin homeostasis and cutaneous inflammatory diseases.

The aryl hydrocarbon receptor (AHR) is widely expressed in immune and non-immune cells of the gut and its activation has been correlated to the outcome of inflammatory bowel diseases (IBD). In ulcerative colitis and Crohn’s disease, there is an excessive chronic inflammation with massive accumulation of leukocytes in the gut, in an attempt to constrain the invasion of pathogenic microorganisms on the damaged organ. Accordingly, it is known that dietary components, xenobiotics, and some chemicals or metabolites can activate AHR and induce the modulation of inflammatory responses. In fact, the AHR triggering by specific ligands during inflammatory conditions results in decreased IFNγ, IL-6, IL-12, TNF, IL-7, and IL-17, along with reduced microbial translocation and fibrosis in the gut. Moreover, upon AHR activation, there are increased regulatory mechanisms such as IL-10, IL-22, prostaglandin E2, and Foxp3, besides the production of anti-microbial peptides and epithelial repair. Most interestingly, commensal bacteria or their metabolites may also activate this receptor, thus contributing to the restoration of gut normobiosis and homeostasis. In line with that, Lactobacillus reuteri, Lactobacillus bulgaricus, or microbial products such as tryptophan metabolites, indole-3-pyruvic acid, urolithin A, short-chain fatty acids, dihydroxyquinoline, and others may regulate the inflammation by mechanisms dependent on AHR activation. Hence, here we discussed the potential modulatory role of AHR on intestinal inflammation, focused on the reestablishment of homeostasis through the receptor triggering by microbial metabolites. Finally, the development of AHR-based therapies derived from bacteria products could represent an important future alternative for controlling IBD.

The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease-especially for its role in modulating immune and inflammatory responses. AHR has been implicated in many diseases that are driven by immune/inflammatory processes, including major depressive disorder, multiple sclerosis, rheumatoid arthritis, asthma, and allergic responses, among others. The mechanisms by which AHR has been suggested to impact immune/inflammatory diseases include targeted gene expression and altered immune differentiation. It has been suggested that single nucleotide polymorphisms (SNPs) that are near AHR-regulated genes may contribute to AHR-dependent disease mechanisms/pathways. Further, we have found that SNPs that are outside of nuclear receptor binding sites (i.e., outside of AHR response elements (AHREs)) may contribute to AHR-dependent gene regulation in a SNP- and ligand-dependent manner. This review will discuss the evidence and mechanisms of AHR contributions to immune/inflammatory diseases and will consider the possibility that SNPs that are outside of AHR binding sites might contribute to AHR ligand-dependent inter-individual variation in disease pathophysiology and response to pharmacotherapeutics.

The gut microbiota and liver cancer have a complex interaction. However, the role of gut microbiome in liver tumor initiation remains unknown. Herein, liver cancer was induced using hydrodynamic transfection of oncogenes to explore liver tumorigenesis in mice. Gut microbiota depletion promoted liver tumorigenesis but not progression. Elevated sterol regulatory element-binding protein 2 (SREBP2) was observed in mice with gut flora disequilibrium. Pharmacological inhibition of SREBP2 or Srebf2 RNA interference attenuated mouse liver cancer initiation under gut flora disequilibrium. Furthermore, gut microbiota depletion impaired gut tryptophan metabolism to activate aryl hydrocarbon receptor (AhR). AhR agonist Ficz inhibited SREBP2 posttranslationally and reversed the tumorigenesis in mice. And, AhR knockout mice recapitulated the accelerated liver tumorigenesis. Supplementation with Lactobacillus reuteri, which produces tryptophan metabolites, inhibited SREBP2 expression and tumorigenesis in mice with gut flora disequilibrium. Thus, gut flora disequilibrium promotes liver cancer initiation by modulating tryptophan metabolism and up-regulating SREBP2.