Search

The reactive oxygen species (ROS)-generating enzyme NOX3 has recently been implicated in the pathophysiology of several acquired forms of sensorineural hearing loss, including cisplatin-, noise- and age-related hearing loss. NOX3 is highly and specifically expressed in the inner ear and therefore represents an attractive target for specific intervention aiming at otoprotection. Despite the strong rationale to inhibit NOX3, there is currently no specific pharmacological inhibitor available. Molecular therapy may represent a powerful alternative. In this study, we developed and tested a collection of small interfering (si) RNA constructs to establish a proof of concept of NOX3 inhibition through local delivery in the mouse inner ear. The inhibitory potential of 10 different siRNA constructs was first assessed in three different cells lines expressing the NOX3 complex. Efficacy of the most promising siRNA construct to knock-down NOX3 was then further assessed

Objective Robust epidemiological and audiological data are needed to prepare for future clinical trials aiming at preventing cisplatin-induced ototoxicity in this suffering cancer population. We precisely assessed the incidence, severity and potential risk factors of symptomatic cisplatin-induced ototoxicity in a large cohort of adults. Methods Retrospective cohort study at a tertiary care university hospital. Study group included 401 consecutive patients over 18 years old treated with cisplatin-based chemotherapy, without concomitant inner ear radiotherapy nor other ototoxic medication. Every participant underwent baseline pre-treatment audiometry and were asked for otological symptoms (tinnitus, hearing loss). If symptomatic, comparative audiometry was performed. Ototoxicity was defined by a threshold shift ≥ 15 dB HL in at least one of the tested frequencies. Results A total of n = 401 cancer patients (59% males) with a mean age of 56 years (range 18–80 years). N = 81 patients (20%) developed symptomatic ototoxicity, affecting predominantly the high frequencies from 4 to 8 kHz. Among the patients with cisplatin-induced hearing loss, n = 49 (60%) experienced simultaneous tinnitus, occurring in over half of them after the first cycle of chemotherapy. None of the analyzed potential risk factors age, gender, smoking, hypertension, diabetes, vasculopathy, dyslipidemia, chemotherapeutic regimen and cumulative cisplatin dose was statistically correlated with the occurrence or severity of cisplatin-induced hearing loss. Conclusion One out of five adult cancer patients treated with cisplatin chemotherapy developed a symptomatic and predominant high-frequency hearing loss, with simultaneous occurrence of tinnitus in over half of them. Standardized audiological monitoring before and during cisplatin chemotherapy allows to quantitatively assess early and objective signs of ototoxicity and offers to optimize anticancer therapy while minimizing morbidity in a multidisciplinary setting.

The reactive oxygen species (ROS)-generating NADPH oxidase NOX3 isoform is highly and specifically expressed in the inner ear. NOX3 is needed for normal vestibular development but NOX-derived ROS have also been implicated in the pathophysiology of sensorineural hearing loss. The role of NOX-derived ROS in noise-induced hearing loss, however, remains unclear and was addressed with the present study. Two different mouse strains, deficient in NOX3 or its critical subunit p22

Warming seas, marine heatwaves, and habitat degradation are increasingly widespread phenomena affecting marine biodiversity, yet our understanding of their broader impacts is largely derived from collective insights from independent localized studies. Insufficient systematic broadscale monitoring limits our understanding of the true extent of these impacts and our capacity to track these at scales relevant to national policies and international agreements. Using an extensive time series of co-located reef fish community structure and habitat data spanning 12 years and the entire Australian continent, we found that reef fish community responses to changing temperatures and habitats are dynamic and widespread but regionally patchy. Shifts in composition and abundance of the fish community often occurred within 2 years of environmental or habitat change, although the relative importance of these two mechanisms of climate impact tended to differ between tropical and temperate zones. The clearest of these changes on temperate and subtropical reefs were temperature related, with responses measured by the reef fish thermal index indicating reshuffling according to the thermal affinities of species present. On low latitude coral reefs, the community generalization index indicated shifting dominance of habitat generalist fishes through time, concurrent with changing coral cover. Our results emphasize the importance of maintaining local ecological detail when scaling up datasets to inform national policies and global biodiversity targets. Scaled-up ecological monitoring is needed to discriminate among increasingly diverse drivers of large-scale biodiversity change and better connect presently disjointed systems of biodiversity observation, indicator research, and governance.

Nearly 460 million individuals are affected by sensorineural hearing loss (SNHL), one of the most common human sensory disorders. In mammals, hearing loss is permanent due to the lack of efficient regenerative capacity of the sensory epithelia and spiral ganglion neurons (SGN). Sphere-forming progenitor cells can be isolated from the mammalian inner ear and give rise to inner ear specific cell types in vitro. However, the self-renewing capacities of auditory progenitor cells from the sensory and neuronal compartment are limited to few passages, even after adding powerful growth factor cocktails. Here, we provide phenotypical and functional characterization of a new pool of auditory progenitors as sustainable source for sphere-derived auditory neurons. The so-called phoenix auditory neuroprogenitors, isolated from the A/J mouse spiral ganglion, exhibit robust intrinsic self-renewal properties beyond 40 passages. At any passage or freezing–thawing cycle, phoenix spheres can be efficiently differentiated into mature spiral ganglion cells by withdrawing growth factors. The differentiated cells express both neuronal and glial cell phenotypic markers and exhibit similar functional properties as mouse spiral ganglion primary explants and human sphere-derived spiral ganglion cells. In contrast to other rodent models aiming at sustained production of auditory neurons, no genetic transformation of the progenitors is needed. Phoenix spheres therefore represent an interesting starting point to further investigate self-renewal in the mammalian inner ear, which is still far from any clinical application. In the meantime, phoenix spheres already offer an unlimited source of mammalian auditory neurons for high-throughput screens while substantially reducing the numbers of animals needed.