ERK1/2 Inhibition via the Oral Administration of Tizaterkib Alleviates Noise-Induced Hearing Loss While Tempering down the Immune Response.

Noise-induced hearing loss (NIHL) is a major cause of hearing impairment and is linked to dementia and mental health conditions, yet no FDA-approved drugs exist to prevent it. Downregulating the mitogen-activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL, but the molecular targets and the mechanism of protection are not fully understood. Here, we tested specifically the role of the kinases ERK1/2 in noise otoprotection using a newly developed, highly specific ERK1/2 inhibitor, tizaterkib, in preclinical animal models. Tizaterkib is currently being tested in phase 1 clinical trials for cancer treatment and has high oral bioavailability and low predicted systemic toxicity in mice and humans. In this study, we performed dose-response measurements of tizaterkib's efficacy against permanent NIHL in adult FVB/NJ mice, and its minimum effective dose (0.5 mg/kg/bw), therapeutic index (>50), and window of opportunity (<48 h) were determined. The drug, administered orally twice daily for 3 days, 24 h after 2 h of 100 dB or 106 dB SPL noise exposure, at a dose equivalent to what is prescribed currently for humans in clinical trials, conferred an average protection of 20-25 dB SPL in both female and male mice. The drug shielded mice from the noise-induced synaptic damage which occurs following loud noise exposure. Equally interesting, tizaterkib was shown to decrease the number of CD45- and CD68-positive immune cells in the mouse cochlea following noise exposure. This study suggests that repurposing tizaterkib and the ERK1/2 kinases' inhibition could be a promising strategy for the treatment of NIHL.

ERK1/2 Inhibition Alleviates Noise-Induced Hearing Loss While Tempering Down the Immune Response.

Noise-induced hearing loss (NIHL) is a major cause of hearing impairment, yet no FDA-approved drugs exist to prevent it. Targeting the mitogen activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL. Tizaterkib is an orally bioavailable, highly specific ERK1/2 inhibitor, currently in Phase-1 anticancer clinical trials. Here, we tested tizaterkib's efficacy against permanent NIHL in mice at doses equivalent to what humans are currently prescribed in clinical trials. The drug given orally 24 hours after noise exposure, protected an average of 20-25 dB SPL in three frequencies, in female and male mice, had a therapeutic window >50, and did not confer additional protection to KSR1 genetic knockout mice, showing the drug works through the MAPK pathway. Tizaterkib shielded from noise-induced cochlear synaptopathy, and a 3-day, twice daily, treatment with the drug was the optimal determined regimen. Importantly, tizaterkib was shown to decrease the number of CD45 and CD68 positive immune cells in the cochlea following noise exposure, which could be part of the protective mechanism of MAPK inhibition.

Thermal dynamics of gold nanoshell dimers under femtosecond laser pulse irradiation: A numerical approach.

We present a numerical investigation of the photothermal response of gold nanoshell (AuNS) dimers when subjected to femtosecond laser pulse irradiation. The time-varying temperature fields for core-shell AuNS dimers are quantified by implementing finite element modeling, integrating the electromagnetic and thermal dual-physics simulations. Given the ultrafast nature of laser pulses, we employ a two-temperature model to accurately portray the energy transfer from excited electrons to the lattice system, a process typically completed post pulse-termination. The temporal analysis of the temperature in the AuNS and the surrounding medium, together with the spatial temperature distribution under different separation distances, elucidates the processes that drive the AuNS dimers' transient temperature distribution and heat dissipation. We report on the critical effects of geometrical parameters on the photothermal response, demonstrating that thinner shells maximize the total deposited energy per unit volume, resulting in increased temperature fields, while decreasing separation distances result in excessive field amplification due to plasmonic modes' production. Our robust numerical approach, enabling simulations with tunable material properties and configurations, may help design nanomaterials with desired features for photothermal cancer treatment and imaging.

Central retinal vein occlusion associated with Bartonella henselae infection.

PURPOSE: To report the clinical features and treatment course of a case of central retinal vein occlusion (CRVO) as the initial sign of ocular Bartonella henselae (B. henselae) infection. OBSERVATION: A 36-year-old male was evaluated for unilateral vision loss. He denied prodromal symptoms but reported prior exposure to fleas. Best corrected visual acuity (BCVA) was 20/400 in the left eye. Clinical examination revealed a CRVO with atypical features including significant peripapillary exudates and peripheral vascular sheathing. Laboratory testing revealed elevated B. henselae IgG titers (1:512) with no abnormalities on hypercoagulability testing. The patient was treated with doxycycline and aflibercept with an excellent clinical response and improvement in BCVA to 20/25 in the left eye two months later. CONCLUSION: CRVO is a rare but sight-threatening complication of ocular bartonellosis and can be the presenting sign of infection, even in the absence of cat exposure or prodromal symptoms.

Molecular dynamics simulations of the human ocular lens with age and cataract.

The human ocular lens consists primarily of elongated, static fibers characterized by high stability and low turnover, which differ dramatically in their composition and properties from other biological membranes. Cholesterol (Chol) and sphingolipids (SL) are present at high concentrations, including saturated SLs, such as dihyrosphingomyelin (DHSM). Past molecular dynamics simulations demonstrated that the presence of DHSM and high Chol concentration contributes to higher order in lipid membranes. This current study simulated more complex models of human lens membranes. Models were developed representing physiological compositions in cataractous lenses aged 74 ± 6 years and in healthy lenses aged 22 ± 4, 41 ± 6, and 69 ± 3 years. With older age, Chol and ceramide concentrations increase and glycerophospholipid concentration decreases. With cataract, ceramide concentration increases and Chol and glycerophospholipid concentrations decrease. Surface area per lipid, deuterium order parameters (SCD), sterol tilt angle, electron density profiles, bilayer thickness, chain interdigitation, two-dimensional radial distribution functions (2D-RDF), lipid clustering, and hydrogen bonding were calculated for all simulations. All systems exhibited low surface area per lipid and high bilayer thickness, indicative of strong vertical packing. SCD parameters suggest similarly, with saturated tails in the hydrophobic core of the membrane having elevated order. Vertical packing and acyl tail order increased with both age and cataract condition. Lateral diffusion decreased with age and cataracts, with the older and cataractous models demonstrating increased long-range structure by the 2D-RDF analysis. In future work examining the membrane proteins of the lens, these models can serve as a physiologically accurate representation of the lens lipidome.

Numerical Study on the Surface Plasmon Resonance Tunability of Spherical and Non-Spherical Core-Shell Dimer Nanostructures.

The near-field enhancement and localized surface plasmon resonance (LSPR) on the core-shell noble metal nanostructure surfaces are widely studied for various biomedical applications. However, the study of the optical properties of new plasmonic non-spherical nanostructures is less explored. This numerical study quantifies the optical properties of spherical and non-spherical (prolate and oblate) dimer nanostructures by introducing finite element modelling in COMSOL Multiphysics. The surface plasmon resonance peaks of gold nanostructures should be understood and controlled for use in biological applications such as photothermal therapy and drug delivery. In this study, we find that non-spherical prolate and oblate gold dimers give excellent tunability in a wide range of biological windows. The electromagnetic field enhancement and surface plasmon resonance peak can be tuned by varying the aspect ratio of non-spherical nanostructures, the refractive index of the surrounding medium, shell thickness, and the distance of separation between nanostructures. The absorption spectra exhibit considerably greater dependency on the aspect ratio and refractive index than the shell thickness and separation distance. These results may be essential for applying the spherical and non-spherical nanostructures to various absorption-based applications.

Dermal absorption study OECD TG 428 mass balance recommendations based on the EFSA database.

The European Food Safety Authority (EFSA) guidance (EFSA, 2017) for dermal absorption (DA) studies recommends stringent mass balance (MB) limits of 95-105%. EFSA suggested that test material can be lost after penetration and requires that for chemicals with <5% absorption the non-recovered material must be added to the absorbed dose if MB is <95%. This has huge consequences for low absorption pesticides. Indeed, one third of the MBs in the EFSA DA database are outside the refined criteria. This is also true for DA data generated by Cosmetics Europe (Gregoire et al., 2019), indicating that this criterion is often not achieved even when using highly standardized protocols. While EFSA hypothesizes that modern analytical and pipetting techniques would enable to achieve this criterion, no scientific basis was provided. We describe how protocol procedures impact MB and evaluate the EFSA DA database to demonstrate that MB is subject to random variation. Generic application of "the addition rule" skews the measured data and increases the DA estimate, which results in unnecessary risk assessment failure. In conclusion, "missing material" is just a random negative deviation to the nominal dose. We propose a data-driven MB criterion of 90-110%, fully in line with OECD recommendations.

Relapsed Burkitt Lymphoma Presenting as an Isolated Infiltrative Optic Neuropathy.

We report a case of relapsed sporadic Burkitt lymphoma (BL) presenting as an isolated infiltrative optic neuropathy. This is a single-patient, retrospective case report of a patient seen by the ophthalmology service at our institution. To our knowledge, our case is the first to report isolated infiltrative optic neuropathy associated with sporadic BL as the sole manifestation of recurrence. The possibility of disease relapse should be considered for patients with a history of lymphoreticular malignancy who present with acute visual symptoms suggestive of optic neuropathy.

RETICULAR PSEUDODRUSEN ON INFRARED IMAGING ARE TOPOGRAPHICALLY DISTINCT FROM SUBRETINAL DRUSENOID DEPOSITS ON EN FACE OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To evaluate the quantitative and topographic relationship between reticular pseudodrusen (RPD) on infrared reflectance (IR) and subretinal drusenoid deposits (SDD) on en face volumetric spectral domain optical coherence tomography. METHODS: Reticular pseudodrusen were marked on IR images by a masked observer. Subretinal drusenoid deposits were visualized on en face sections of spectral domain optical coherence tomography below the external limiting membrane and identified by a semiautomated technique. Control RPD lesions were generated in a random distribution for each IR image. Binary maps of control and experimental RPD and SDD were merged and analyzed in terms of topographic localization and quantitative drusen load comparison. RESULTS: A total of 54 eyes of 41 patients diagnosed with RPD were included in this study. The average number of RPD lesions on IR images was 320 ± 44.62 compared with 127 ± 26.02 SDD lesions on en face (P < 0.001). The majority of RPD lesions did not overlap with SDD lesions and were located >30 µm away (92%). The percentage of total SDD lesions overlapping RPD was 2.91 ± 0.87% compared with 1.73 ± 0.68% overlapping control RPD lesions (P < 0.05). The percentage of total SDD lesions between 1 and 3 pixels of the nearest RPD lesion was 5.08 ± 1.40% compared with 3.33 ± 1.07% between 1 and 3 pixels of the nearest control RPD lesion (P < 0.05). CONCLUSION: This study identified significantly more RPD lesions on IR compared with SDD lesions on en face spectral domain optical coherence tomography and found that a large majority of SDD (>90% of lesions) were >30 µm away from the nearest RPD. Together, our findings indicate that RPD and SDD are two entities that are only occasionally topographically associated, suggesting that at some stage in their development, they may be pathologically related.

Detection of fish antigens aerosolized during fish processing using newly developed immunoassays.

BACKGROUND: Aerosolization of fish proteins during seafood processing has been identified as a potential route for allergic sensitization and occupational asthma among workers involved in high-risk activities. The aim of this study was to develop immunological assays for the quantification of aerosolized fish antigens in a fish-processing factory. METHODS: Polyclonal antibodies to the main fish species processed in the factory (anchovy and pilchard) were generated in rabbits and compared by ELISA inhibition assay and immunoblotting. These antisera were utilized to develop ELISA assays for the detection of fish antigens. The ELISA inhibition assays were evaluated by analyzing environmental air samples collected from three areas in a fish-processing factory: pilchard canning, fish meal production and lobster processing. RESULTS: By immunoblotting, the rabbit polyclonal antibodies demonstrated IgG antibody binding patterns comparable with IgE antibodies of fish-sensitized patients, particularly in regard to the major fish allergens parvalbumins. The sensitivity of the fish-specific ELISA assays developed was 0.5 microg/ml. The ELISA inhibition assays were able to differentiate between the two different fish species of interest but did not recognize a crustacean species. Notable differences in exposure levels to canned pilchard and anchovy antigens were demonstrated in the three different working areas of the factory, with assays having a detection limit as low as 105 ng/m(3). CONCLUSION: These ELISA-based assays are sensitive and specific to quantify differential exposure levels to fish antigens produced during fish processing, making it possible to investigate exposure-disease response relationships among workers in this industry.