Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

Mitochondrial Membrane Permeabilization in Cell Death

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

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European Position Paper on Rhinosinusitis and Nasal Polyps 2020

On allergic rhinitis

Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials

One of the mechanisms by which chemotherapeutics destroy cancer cells is by inducing apoptosis. Apoptosis can be activated through several different signalling pathways, but these all appear to converge at a single event - mitochondrial membrane permeabilization (MMP). This 'point-of-no-return' in the cell death program is a complex process that is regulated by the composition of the mitochondrial membrane and pre-mitochondrial signal-transduction events. MMP is subject to a complex regulation, and local alterations in the composition of mitochondrial membranes, as well as alterations in pre-mitochondrial signal-transducing events, can determine chemotherapy resistance in cancer cells. Detecting MMP might thus be useful for detecting chemotherapy responses in vivo. Several cytotoxic drugs induce MMP by a direct action on mitochondria. This type of agents can enforce death in cells in which upstream signals normally leading to apoptosis have been disabled. Cytotoxic components acting on mitochondria can specifically target proteins from the Bcl-2 family, the peripheral benzodiazepin receptor, or the adenine nucleotide translocase, and/or act by virtue of their physicochemical properties as steroid analogues, cationic ampholytes, redox-active compounds or photosensitizers. Some compounds acting on mitochondria can overcome the cytoprotective effect of Bcl-2-like proteins. Several agents which are already used in anti-cancer chemotherapy can induce MMP, and new drugs specifically designed to target mitochondria are being developed.

Chemotherapy: targeting the mitochondrial cell death pathway.

ObjectiveTo provide a comprehensive state-of-the-art review of the emerging role of urine leukotriene E4 (uLTE4) as a biomarker in the diagnosis of chronic rhinosinusitis (CRS), aspirin-exacerbated...

Urine Leukotriene E4: Implications as a Biomarker in Chronic Rhinosinusitis.

Immunology-based recommendations for available and upcoming biologics in aspirin-exacerbated respiratory disease.

Importance Specific temporal goals for treatment of head and neck cancer (HNC) are common in Europe but not in the United States. We implemented a patient-centric navigation model with an aspirational goal that all patients will receive treatment recommendations within 2 weeks of presentation as a means to improve outcomes in our patients with HNC. Objective To assess the temporal impact of using an aspirational goal in a patient-centric navigation system on the time from presentation to formulation of treatment planning for patients with HNC. Design, Setting, and Participants Retrospective review of 100 consecutive patients treated for squamous cell carcinoma of the head and neck at a tertiary referral center between 2011 and 2014. Patients were assessed to determine the efficiency of a patient-centric navigational model in delivering cancer treatment recommendations. This model was designed with an aspirational goal of providing treatment recommendations within a 2-week period. Exposure Starting in 2011, patient-centric navigation model including the assignment of a nurse who acts as a patient navigator. Main Outcomes and Measures The time interval between presentation to clinic and definitive treatment recommendations, as well as factors associated with delay. Results Of the 93 patients who met inclusion requirements, most were white (81 [87%]) males (74 [80%]) with a mean (SD) age of 63.4 (10.8) years insured by Medicare or Medicaid (64 [69%]). Forty-seven (51%) received treatment recommendations within the 2-week period, with median and mode values of 15 and 14 days, respectively. The mean (SD) interval was 18.8 (18.6) days. Outliers included 2 patients with synchronous lung nodules (72 and 85 days) and 2 patients with psychosocial barriers (107 and 86 days). There were no significant differences seen for the mean (SD) time interval with respect to patient race (blacks, 17.6 [15.7] vs whites, 22.5 [30.0]; P  = .20), sex (males, 18.3 [18.1] vs females, 20.4 [19.7]; P  = .13), insurance status (insured, 16.3 [10.2] vs uninsured, 19.8 [21.0]; P  = .24), and stage at presentation (stage I, 14.4 [17.0] vs stage II, 11.0 [5.3] vs stage III, 14.7 [8.6] vs stage IV, 21.2 [20.2]; P  = .40). Conclusions and Relevance The goal of treatment recommendations for HNC within 2 weeks was shown to be reasonable and attainable. Further research should address the delays encountered by patients with psychosocial barriers and those with synchronous lung nodules.

/pdf/initial-experience-of-a-patient-navigation-model-for-head-4cm9l88cpb.pdf

Initial Experience of a Patient Navigation Model for Head and Neck Cancer.

BackgroundChronic rhinosinusitis with nasal polyps (CRSwNPs) has several phenotypes.ObjectivesThe goal of this study was to evaluate computed tomography (CT) findings associated with each CRSwNP ph...

Joshua M. Levy

Papers

Urine Leukotriene E4: Implications as a Biomarker in Chronic Rhinosinusitis.

Immunology-based recommendations for available and upcoming biologics in aspirin-exacerbated respiratory disease.

Initial Experience of a Patient Navigation Model for Head and Neck Cancer.

Computed Tomography Findings Can Help Identify Different Chronic Rhinosinusitis With Nasal Polyp Phenotypes.

COVID-19 survivorship: How otolaryngologist-head and neck surgeons can restore quality of life after critical illness.