Comorbidities and Laryngeal Cancer in Patients with Obstructive Sleep Apnea: A Review.

Introductions: The global prevalence of obstructive sleep apnea shows that this disease appears in 1 billion people, with the prevalence exceeding 50% in some countries. Treatment is necessary to minimize negative health impacts. Obstructive sleep apnea (OSA) is defined as a cause of daytime sleepiness, as well as a clinical manifestation of sleep-disordered breathing. In the literature, there are numerous controversial studies regarding the etiology of this condition, but it is universally accepted that reduced activity in the upper airway muscles plays a significant role in its onset. Additionally, OSA has been associated with a series of comorbidities, such as type II diabetes, metabolic syndrome, and cardiovascular and pulmonary conditions, as well as head and neck tumors, especially oropharyngeal and laryngeal tumors. This is a review of the subject of OSA that considers several aspects: an analysis of the comorbidities associated with OSA, the involvement of tumor pathology in the onset of OSA, and the association of OSA with various types of laryngeal cancers. Additionally, it includes an evaluation of postoperative and medical outcomes for patients with OSA and laryngeal tumors treated surgically and medically, including chemotherapy. Relevant Sections: By taking into consideration the stated objective, a systematic analysis of the available literature was conducted, encompassing the PubMed, Medline, and Scopus databases. The evaluation was based on several keywords, including head and neck cancer, diabetes, diabetic, overlap syndrome, cardiovascular conditions, laryngeal neoplasm, radiotherapy, and chemotherapy, as well as the concept of quality of life in laryngectomized patients and patients with OSA. Discussions: The review evaluates the involvement of OSA in the presence of comorbidities, as well as the increased incidence of OSA in patients with laryngeal cancer. It is important to note that surgical and post-surgical treatment can play a significant role in triggering OSA in these patients. Conclusions: The studies regarding the correlations between OSA, comorbidities, and head and neck tumors indicate a significantly increased risk of OSA in association with conditions such as diabetes, metabolic syndrome, cardiovascular diseases, and head and neck tumors, particularly laryngeal tumors. This association has a physio-pathological basis. The various surgical methods followed by radiation and chemotherapy for tumor treatment do not exclude an increased risk of developing OSA after treatment. This significantly influences the quality of life of patients who survive these types of tumors. Future directions: Due to the multiple comorbidities associated with OSA, the extension of polysomnography associated with investigations during sleep, such as drug-induced sleep endoscopy, represents a tendency for the early diagnosis of this pathology, which affects the quality of life of these patients. Patients with head and neck cancer are at high risk of developing obstructive sleep apnea; this is why it is necessary to expand the polysomnographic investigation of these patients after surgical procedures or after radiotherapy and chemotherapy.

Evaluating the impact of skill development for drowning prevention: a relationship-building approach to community engagement.

OBJECTIVE: Evaluate the impact of a broadened theoretical and empirical model of community engagement aimed at coastal drowning prevention via relationship building between lifeguards and beachgoers through the delivery of skill development sessions on the beach. SETTING: A lifeguard-patrolled beach in Lorne, Victoria, Australia, during the 2023 peak summer holiday season. METHODS: In total, 12 skill development sessions were delivered by teams of lifeguards and risk researchers to beachgoers. Sessions were codesigned by the research team and shared with lifeguards beforehand to review and include lifeguards' interpretations of localised risk during delivery. In total, 85 survey interviews were conducted with self-selecting beachgoers post participation. RESULTS: In total, 79 participants (93%) enjoyed participating in the session(s) and 77 participants (91%) reported learning something new. Learning how to identify rip current (n=59) and escape a rip current (n=40) were the two most commonly learnt skills. Participants' intended changes in future beachgoing behaviours (n=46) include asking lifeguards at patrolled beaches how to identify site-specific (rip current) risk (n=11) and attempting to identify a rip current before entering the water (n=10). The spillover effects of participation include sharing what participants had learnt with family and friends. CONCLUSIONS: Creating a dialogic model of collaboration via participatory community engagements between lifeguards and researchers with the beachgoing public can successfully prompt learning drowning prevention skills. These skills are required when navigating dynamic coastal hazards at unpatrolled beaches. Supporting lifeguards and life-savers to provide skill development expands the ways that life-saving services can engage the public, including measurement of lifeguards' contributions to coastal drowning prevention.

Physiological background of the remarkably high Cd2+ tolerance of the Aspergillus fumigatus Af293 strain.

The physiological background of the unusually high cadmium tolerance (MIC50 > 2 mM) of Aspergillus fumigatus Af293 was investigated. The cadmium tolerance of the tested environmental and clinical A. fumigatus strains varied over a wide range (0.25 mM < MIC50 < 1 mM). Only the Af293 strain showed a MIC50 value of >2 mM, and this phenotype was accompanied by increased in vivo virulence in mice. A strong correlation was found between the cadmium tolerance and the transcription of the pcaA gene, which encodes a putative cadmium efflux pump. The cadmium tolerance also correlated with the iron tolerance and the extracellular siderophore production of the strains. In addition to these findings, Af293 did not show the synergism between iron toxicity and cadmium toxicity that was detected in the other strains. Based on these results, we suggest that the primary function of PcaA should be acting as a ferrous iron pump and protecting cells from iron overload. Nevertheless, the heterologous expression of pcaA may represent an attractive strain improvement strategy to construct fungal strains for use in biosorption or biomining processes or to prevent accumulation of this toxic metal in crops.

Anti-inflammatory Mechanisms Triggered by Apoptotic Cells during Their Clearance.

In the human body, billions of cells die by apoptosis every day. The subsequent clearance of apoptotic cells by phagocytosis is normally efficient enough to prevent secondary necrosis and the consequent release of cell contents that would induce inflammation and trigger autoimmunity. In addition, apoptotic cells generally induce an anti-inflammatory response, thus removal of apoptotic cells is usually immunologically silent. Since the first discovery that uptake of apoptotic cells leads to transforming growth factor (TGF)-ß and interleukin (IL)-10 release by engulfing macrophages, numerous anti-inflammatory mechanisms triggered by apoptotic cells have been discovered, including release of anti-inflammatory molecules from the apoptotic cells, triggering immediate anti-inflammatory signaling pathways by apoptotic cell surface molecules via phagocyte receptors, activating phagocyte nuclear receptors following uptake and inducing the production of anti-inflammatory soluble mediators by phagocytes that may act via paracrine or autocrine mechanisms to amplify and preserve the anti-inflammatory state. Here, we summarize our present knowledge about how these anti-inflammatory mechanisms operate during the clearance of apoptotic cells.

Involvement of adenosine A3 receptors in the chemotactic navigation of macrophages towards apoptotic cells.

The first step in the clearance of apoptotic cells is chemotactic migration of macrophages towards the apoptotic cells guided by find-me signals provided by the dying cells. Upon sensing the chemotactic signals, macrophages release ATP. ATP is then degraded to ADP, AMP and adenosine to trigger purinergic receptors concentrated at the leading edge of the cell. Previous studies have shown that in addition to the chemotactic signals, this purinergic autocrine signaling is required to amplify and translate chemotactic signals into directional motility. In the present study the involvement of adenosine A3 receptors (A3R) was studied in the chemotactic migration of macrophages directed by apoptotic thymocyte-derived find-me signals. By taking video images in vitro, we demonstrate 1, by administering apyrase, which degrades ATP and ADP, that the purinergic autocrine signaling is required for maintaining both the velocity and the directionality of macrophage migration towards the apoptotic thymocytes; 2, by readding 5'-N-ethylcarboxamidoadenosine, an adenosine analogue, to apyrase treated cells that the adenosine receptor signaling alone is sufficient to act so; and 3, by studying migration of various adenosine receptor null or adenosine receptor antagonist-treated macrophages, that the individual loss of the A3R signaling leads to the loss of chemotactic navigation. Though loss of A3Rs does not affect the phagocytotic capacity of macrophages, intraperitoneally-injected apoptotic thymocytes were cleared with a delayed kinetics by A3R null macrophages in vivo due to the impaired chemotactic navigation. All together these data demonstrate the involvement of macrophage A3Rs in the proper chemotactic navigation and consequent in vivo clearance of apoptotic cells. Interestingly, loss of A3Rs did not affect the in vivo clearance of apoptotic thymocytes in the dexamethasone-treated thymus.

Adenosine A2A receptor signaling attenuates LPS-induced pro-inflammatory cytokine formation of mouse macrophages by inducing the expression of DUSP1.

Adenosine is known to reduce inflammation by suppressing the activity of most immune cells. Previous studies have shown that lipopolysaccharide (LPS) stimulated mouse macrophages produce adenosine, and the adenosine A2A receptor (A2AR) signaling activated in an autocrine manner attenuates LPS-induced pro-inflammatory cytokine formation. It has been suggested that A2AR signaling inhibits LPS-induced pro-inflammatory cytokine production through a unique cAMP-dependent, but PKA- and Epac-independent signaling pathway. However, the mechanism of inhibition was not identified so far. Here we report that LPS stimulation enhances A2AR expression in mouse bone marrow derived macrophages, and loss of A2ARs results in enhanced LPS-induced pro-inflammatory response. Loss of A2ARs in A2AR null macrophages did not alter the LPS-induced NF-κB activation, but an enhanced basal and LPS-induced phosphorylation of MAP kinases (especially that of JNKs) was detected in A2AR null cells. A2AR signaling did not alter the LPS-induced phosphorylation of their upstream kinases, but by regulating adenylate cyclase activity it enhanced the expression of dual specific phosphatase (DUSP)1, a negative regulator of MAP kinases. As a result, lower basal and LPS-induced DUSP1 mRNA and protein levels can be detected in A2AR null macrophages. Silencing of DUSP1 mRNA expression resulted in higher basal and LPS-induced JNK phosphorylation and LPS-induced pro-inflammatory cytokine formation in wild type macrophages, but had no effect on that in A2AR null cells. Our data indicate that A2AR signaling regulates both basal and LPS-induced DUSP1 levels in macrophages via activating the adenylate cyclase pathway.

Transmembrane TNF-α Reverse Signaling Inhibits Lipopolysaccharide-Induced Proinflammatory Cytokine Formation in Macrophages by Inducing TGF-ß: Therapeutic Implications.

TNF-α, a potent proinflammatory cytokine, is generated in a precursor form called transmembrane (m)TNF-α that is expressed as a type II polypeptide on the surface of certain cells. mTNF-α was shown to act both as a ligand by binding to TNF-α receptors, as well as a receptor that transmits outside-to-inside (reverse) signals back into the mTNF-α-bearing cells. In this study, we show that nonactivated macrophages express basal levels of mTNF-α and respond to anti-TNF-α Abs by triggering the MAPK kinase 4 signaling pathway. The pathway induces TGF-ß. Based on inhibitory experiments, the production of TGF-ß1 is regulated via Jun kinases, whereas that of other TGF-ßs is regulated via p38 MAPKs. Exposure to LPS further induced the expression of mTNF-α, and triggering of mTNF-α strongly suppressed the LPS-induced proinflammatory response. Neutralizing TGF-ß by Abs prevented the mTNF-α-mediated suppression of LPS-induced proinflammatory cytokine formation, indicating that the immune-suppressive effect of mTNF-α is mediated via TGF-ß. Although apoptotic cells are also known to suppress LPS-induced proinflammatory cytokine formation in macrophages by upregulating TGF-ß, we show that they do not use the mTNF-α signaling pathway. Because TGF-ß possesses a wide range of immune-suppressive effects, our data indicate that upregulation of TGF-ß synthesis by those TNF-α-targeting molecules, which are able to trigger mTNF-α, might contribute to their therapeutic effect in the treatment of certain inflammatory diseases such as Crohn's disease, Wegener's granulomatosis, or sarcoidosis. Additionally, none of the TNF-α-targeting molecules is expected to interfere with the immune-silencing effects of apoptotic cells.

Retinoids induce Nur77-dependent apoptosis in mouse thymocytes.

Nur77 is a transcription factor, which plays a determinant role in mediating T cell receptor-induced cell death of thymocytes. In addition to regulation of transcription, Nur77 contributes to apoptosis induction by targeting mitochondria, where it can convert Bcl-2, an anti-apoptotic protein into a proapoptotic molecule. Previous studies have demonstrated that retinoids are actively produced in the mouse thymus and can induce a transcription-dependent apoptosis in mouse thymocytes. Here we show that retinoic acids induce the expression of Nur77, and retinoid-induced apoptosis is completely dependent on Nur77, as retinoids were unable to induce apoptosis in Nur77 null thymocytes. In wild-type thymocytes retinoids induced enhanced expression of the apoptosis-related genes FasL, TRAIL, NDG-1, Gpr65 and Bid, all of them in a Nur77-dependent manner. The combined action of these proteins led to Caspase 8-dependent Bid cleavage in the mitochondria. In addition, we could demonstrate the Nur77-dependent induction of STAT1 leading to enhanced Bim expression, and the mitochondrial translocation of Nur77 leading to the exposure of the Bcl-2/BH3 domain. The retinoid-induced apoptosis was dependent on both Caspase 8 and STAT1. Our data together indicate that retinoids induce a Nur77-dependent cell death program in thymocytes activating the mitochondrial pathway of apoptosis.

Macrophages engulfing apoptotic thymocytes produce retinoids to promote selection, differentiation, removal and replacement of double positive thymocytes.

The thymus provides the microenvironment in which thymocytes develop into mature T-cells, and interactions with thymic stromal cells are thought to provide the necessary signals for thymocyte maturation. Recognition of self-MHC by T-cells is a basic requirement for mature T-cell functions, and those thymocytes that do not recognize or respond too strongly to the peptide-loaded self-MHC molecules found in the thymus undergo apoptosis. As a result, 95% of the thymocytes produced will die and be subsequently cleared by macrophages. This review describes a complex crosstalk between developing thymocytes and engulfing macrophages which is mediated by retinoids produced by engulfing macrophages. The interaction results in the harmonization of the rate of cell death of dying double positive cells with their clearance and replacement, and in promotion of the differentiation of the selected cells in the thymus.

Retinoids produced by macrophages engulfing apoptotic cells contribute to the appearance of transglutaminase 2 in apoptotic thymocytes.

Transglutaminase 2 (TG2) has been known for a long time to be associated with the in vivo apoptosis program of various cell types including T cells. Though the expression of the enzyme was strongly induced in mouse thymocytes following apoptosis induction in vivo, no significant induction of TG2 could be detected, when thymocytes were induced to die by the same stimuli in vitro indicating that signals arriving from the tissue environment are required for the in vivo induction of the enzyme in apoptotic thymocytes. Previous studies have shown that one of these signals is transforming growth factor-ß (TGF-ß) which is released by macrophages engulfing apoptotic cells. Besides TGF-ß, the TG2 promoter contains retinoic acid response elements as well. Here we show that in vitro retinoic acids, or TGF-ß and retinoic acids together can significantly enhance the TG2 mRNA expression in dying thymocytes, and the apoptotic signal contributes to the TG2 induction. Inhibition of retinoic acid synthesis either by alcohol or retinaldehyde dehydrogenases significantly attenuates the in vivo induction of TG2 following apoptosis induction indicating that retinoids indeed might contribute in vivo to the apoptosis-related TG2 expression. What is more, the in vivo apoptosis induction in the thymus is accompanied by an enhanced retinoid-dependent transcriptional activity due to the enhanced retinoid synthesis by macrophages engulfing apoptotic cells. Our data reveal a new crosstalk between macrophages and apoptotic cells, in which apoptotic cell uptake-induced retinoid synthesis in macrophages enhances TG2 expression in the dying thymocytes.