Inhibition of EIF2α Dephosphorylation Decreases Cell Viability and Synergizes with Standard-of-Care Chemotherapeutics in Head and Neck Squamous Cell Carcinoma.

Drug resistance is a common cause of therapy failure in head and neck squamous cell carcinoma (HNSCC). One approach to tackling it is by targeting fundamental cellular processes, such as translation. The eukaryotic translation initiation factor 2α (EIF2α) is a key player in canonical translation initiation and integrates diverse stress signals; when phosphorylated, it curbs global protein synthesis. This study evaluates EIF2α expression and phosphorylation in HNSCC. A small-molecule inhibitor of EIF2α dephosphorylation, salubrinal, was tested in vitro, followed by viability assays, flow cytometry, and immunoblot analyses. Patient-derived 3D tumor spheres (PD3DS) were cultured with salubrinal and their viability assessed. Lastly, salubrinal was evaluated with standard-of-care chemotherapeutics. Our analysis of RNA and proteomics data shows elevated EIF2α expression in HNSCC. Immunohistochemical staining reveals increasing EIF2α abundance from premalignant lesions to invasive and metastatic carcinoma. In immunoblots from intraoperative samples, EIF2α expression and steady-state phosphorylation are higher in HNSCC than in neighboring normal tissue. Inhibition of EIF2α dephosphorylation decreases HNSCC cell viability and clonogenic survival and impairs the G1/S transition. Salubrinal also decreases the viability of PD3DS and acts synergistically with cisplatin, 5-fluorouracil, bleomycin, and proteasome inhibitors. Our results indicate that pharmacological inhibition of EIF2α dephosphorylation is a potential therapeutic strategy for HNSCC.

Treatment Results of Endoscopic Transnasal Orbital Decompression for Graves' Orbitopathy-A Single-Center Retrospective Analysis in 28 Orbits of 16 Patients.

Graves' orbitopathy (GO) is an extrathyroidal manifestation of Graves' disease (GD), which can be associated with corneal ulcerations or optic neuropathy in severe forms. Transnasal endoscopic orbital decompression (TEOD) is a surgical procedure performed in order to decrease the intraorbital pressure by removing part of its bony borders in cases with excessive mass in orbit. The aim of this study was to present the results and evaluate the efficacy of TEOD for GO. The retrospective study included 28 orbits (16 patients) who underwent TEOD from 2017 to 2020. Outcome was evaluated based on visual acuity improvement, clinical activity score (CAS) decrease, proptosis, and intraocular pressure (IOP) reduction. A preoperative best-corrected visual acuity (BCVA) increased from 0.69 ± 0.385 (mean ± standard deviation) to 0.74 ± 0.332 (p = 0.17) postoperatively. CAS decreased in 15 orbits postoperatively. Proptosis decreased from 22.89 ± 1.873 mm to 21.25 ± 2.053 mm (p < 0.05). IOP decreased from a preoperative 16.11 ± 3.93 mmHg to 14.40 ± 3.27 mmHg (p < 0.05) postoperatively. In addition, postoperative relief of exposure keratitis was observed. The analysis of development of iatrogenic diplopia revealed increasing in degree of diplopia. TEOD shows rare complications, but significant improvements in BCVA, CAS, proptosis, and IOP.

HIF1, HSF1, and NRF2: Oxidant-Responsive Trio Raising Cellular Defenses and Engaging Immune System.

Cellular homeostasis is continuously challenged by damage from reactive oxygen species (ROS) and numerous reactive electrophiles. Human cells contain various protective systems that are upregulated in response to protein damage by electrophilic or oxidative stress. In addition to the NRF2-mediated antioxidant response, ROS and reactive electrophiles also activate HSF1 and HIF1 that control heat shock response and hypoxia response, respectively. Here, we review chemical and biological mechanisms of activation of these three transcription factors by ROS/reactive toxicants and the roles of their gene expression programs in antioxidant protection. We also discuss how NRF2, HSF1, and HIF1 responses establish multilayered cellular defenses consisting of largely nonoverlapping programs, which mitigates limitations of each response. Some innate immunity links in these stress responses help eliminate damaged cells, whereas others suppress deleterious inflammation in normal tissues but inhibit immunosurveillance of cancer cells in tumors.

Heat Shock Proteins and HSF1 in Cancer.

Fitness of cells is dependent on protein homeostasis which is maintained by cooperative activities of protein chaperones and proteolytic machinery. Upon encountering protein-damaging conditions, cells activate the heat-shock response (HSR) which involves HSF1-mediated transcriptional upregulation of a group of chaperones - the heat shock proteins (HSPs). Cancer cells experience high levels of proteotoxic stress due to the production of mutated proteins, aneuploidy-induced excess of components of multiprotein complexes, increased translation rates, and dysregulated metabolism. To cope with this chronic state of proteotoxic stress, cancers almost invariably upregulate major components of HSR, including HSF1 and individual HSPs. Some oncogenic programs show dependence or coupling with a particular HSR factor (such as frequent coamplification of HSF1 and MYC genes). Elevated levels of HSPs and HSF1 are typically associated with drug resistance and poor clinical outcomes in various malignancies. The non-oncogene dependence ("addiction") on protein quality controls represents a pancancer target in treating human malignancies, offering a potential to enhance efficacy of standard and targeted chemotherapy and immune checkpoint inhibitors. In cancers with specific dependencies, HSR components can serve as alternative targets to poorly druggable oncogenic drivers.

The Emerging Role of Small Extracellular Vesicles in Inflammatory Airway Diseases.

Extracellular vesicles (EVs) are produced and released by all cells and are present in all body fluids. They exist in a variety of sizes, however, small extracellular vesicles (sEVs), the EV subset with a size range from 30 to 150 nm, are of current interest. By transporting a complex cargo that includes genetic material, proteins, lipids, and signaling molecules, sEVs can alter the state of recipient cells. The role of sEVs in mediating inflammatory processes and responses of the immune system is well-documented, and adds another layer of complexity to our understanding of frequent diseases, including chronic rhinosinusitis (CRS), asthma, chronic obstructive pulmonary disease (COPD), and upper airway infections. In these diseases, two aspects of sEV biology are of particular interest: (1) sEVs might be involved in the etiopathogenesis of inflammatory airway diseases, and might emerge as attractive therapeutic targets, and (2) sEVs might be of diagnostic or prognostic relevance. The purpose of this review is to outline the biological functions of sEVs and their capacity to both augment and attenuate inflammation and immune response in the context of pathogen invasion, CRS, asthma, and COPD.

Tympanometric evaluation of Eustachian tube function in Polish scuba divers.

BACKGROUND: Scuba divers are subjected to relatively high ambient pressures while descending. Equalizing maneuvers (e.g., Valsalva) are necessary to open the Eustachian tube (ET) and allow air into the middle ear (ME) cavity. Insufficient opening of the ET leads to ME barotrauma, which is the most common injury related to scuba diving. The study aims were to assess the incidence of ME barotrauma and to compare tympanometric parameters and stapedial reflexes in scuba divers and non-diving individuals. MATERIAL AND METHODS:: 60 scuba divers participated in the study; control consisted of 90 non-diving volunteers without a history of otolaryngologic problems. All participants were examined with the use of otoscopy and tympanometry with evaluation of ipsilateral stapedial reflexes. The group studied was surveyed regarding occurrence of ME barotrauma and diving competence. RESULTS: 51.7% of the divers experienced ME barotrauma, the most common symptoms being earache and hearing loss. Comparison of the group studied and control revealed significantly lower ME pressure and compliance in scuba divers. In scuba divers with ME barotrauma, longer time from injury correlates directly with greater ME pressure and compliance, indicating tissue recovery. At 4,000Hz 100dB percentage of present stapedial reflexes among scuba divers was significantly lower than in controls; moreover, a greater number of dives correlated inversely with percentage of present stapedial reflexes at 4000Hz 100dB. The reduced thresholds at high intensities suggest a negative effect of scuba diving on hearing. CONCLUSIONS: ME pressure and compliance, however still within the norm, are significantly lower in scuba divers than in non-diving healthy volunteers. This may be attributed to a subclinical form of barotrauma.

Internal Carotid Artery Aneurysm Mimicking Peritonsillar Abscess.

The extracranial internal carotid artery aneurysm (EICAA) is an uncommon arterial lesion. Patients typically present with neurologic symptoms resulting from impaired cerebral perfusion and compression symptoms of cranial nerves. Often EICAA presents as a pulsatile neck mass, which is otherwise asymptomatic. We present a case of an 84-year-old female, who was initially referred to the Emergency Department for Otolaryngology with suspected peritonsillar abscess. The patient had a history of recent upper airway infection and cardiovascular comorbidities, including hypertension and ischaemic stroke complicated by extensive neurologic deficits. Physical examination revealed a compact, nonpulsatile mass in the lateral parapharyngeal space and local erythema of the mucosa. Duplex Doppler Ultrasonography and Computed Tomography revealed an atherosclerotic aneurysm of the right internal carotid artery, measuring 63 × 55 × 88 mm, stretching from the skull base to the angle of the mandible.