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Glaucoma is a neurodegenerative disease that affects the retinal ganglion cells (RGCs). The main risk factor is elevated intraocular pressure (IOP), but the actual cause of the disease remains unknown. Emerging evidence indicates that metabolic dysfunction plays a central role. The aim of the current study was to determine and compare the effect of universal hypoxia on the metabolomic signature in plasma samples from healthy controls (n = 10), patients with normal-tension glaucoma (NTG, n = 10), and ocular hypertension (OHT, n = 10). By subjecting humans to universal hypoxia, we aim to mimic a state in which the mitochondria in the body are universally stressed. Participants were exposed to normobaric hypoxia for two hours, followed by a 30 min recovery period in normobaric normoxia. Blood samples were collected at baseline, during hypoxia, and in recovery. Plasma samples were analyzed using a non-targeted metabolomics approach based on liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). Multivariate analyses were conducted using principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), and univariate analysis using the Wilcoxon signed-rank test and false discovery rate (FDR) correction. Unique metabolites involved in fatty acid biosynthesis and ketone body metabolism were upregulated, while metabolites of the kynurenine pathway were downregulated in OHT patients exposed to universal hypoxia. Differential affection of metabolic pathways may explain why patients with OHT initially do not suffer or are more resilient from optic nerve degeneration. The metabolomes of NTG and OHT patients are regulated differently from control subjects and show dysregulation of metabolites important for energy production. These dysregulated processes may potentially contribute to the elevation of IOP and, ultimately, cell death of the RGCs.

The main risk factor for primary open-angle glaucoma (POAG) is increased intraocular pressure (IOP). It is of interest that about half of the patients have an IOP within the normal range (normal-tension glaucoma, NTG). Additionally, there is a group of patients with a high IOP but no glaucomatous neurodegeneration (ocular hypertension, OHT). Therefore, risk factors other than IOP are involved in the pathogenesis of glaucoma. Since the retina has a very high oxygen-demand, decreased autoregulation and a fluctuating oxygen supply to the retina have been linked to glaucomatous neurodegeneration. To assess the significance of these mechanisms, we have utilized a human experimental model, in which we stress participants with a fluctuating oxygen supply. Levels of oxidative stress molecules, antioxidants, and lipid mediators were measured in the plasma. Patients with NTG, OHT, and control subjects were found to have similar levels of oxidative stress markers. In contrast, patients with OHT had a higher level of total antioxidant capacity (TAC) and pro-homeostatic lipid mediators. Thus, we suggest that OHT patients manage fluctuating oxygen levels more efficiently and, thus, are less susceptible to glaucomatous neurodegenerations, due to enhanced systemic antioxidant protection.

Distant progression (DP) in oropharyngeal squamous cell carcinoma (OPSCC) has significant impact on morbidity and mortality. This study systematically reviewed the literature on studies reporting location and timing of DP after human papillomavirus (HPV)+ or HPV- OPSCCs. PubMed, EMBASE, and the Cochrane Library were systematically searched for studies reporting DP in patients treated with curative intend for an OPSCC. Outcome was site of and time to DP stratified on HPV-status. Seven studies (n = 1564; 77% HPV+) were included in which 313 patients (20%) developed a DP (70% HPV+). The most common site of DP was the lungs (n = 232) regardless of HPV-status. Patients with HPV+ tumors were more prone to dissemination involving multiple sites (risk ratio = 16.49). There was no difference in time to DP when stratified on HPV-status (P = .10). The pattern of but not time to DP was significantly different in patients with OPSCC when stratified on HPV-status.