Cationic Mucic Acid Polymer-Based siRNA Delivery Systems.

Nanoparticle (NP) delivery systems for small interfering RNA (siRNA) that have good systemic circulation and high nucleic acid content are highly desired for translation into clinical use. Here, a family of cationic mucic acid-containing polymers is synthesized and shown to assemble with siRNA to form NPs. A cationic mucic acid polymer (cMAP) containing alternating mucic acid and charged monomers is synthesized. When combined with siRNA, cMAP forms NPs that require steric stabilization by poly(ethylene glycol) (PEG) that is attached to the NP surface via a 5-nitrophenylboronic acid linkage (5-nitrophenylboronic acid-PEGm (5-nPBA-PEGm)) to diols on mucic acid in the cMAP in order to inhibit aggregation in biological fluids. As an alternative, cMAP is covalently conjugated with PEG via two methods. First, a copolymer is prepared with alternating cMAP-PEG units that can form loops of PEG on the surface of the formulated siRNA-containing NPs. Second, an mPEG-cMAP-PEGm triblock polymer is synthesized that could lead to a PEG brush configuration on the surface of the formulated siRNA-containing NPs. The copolymer and triblock polymer are able to form stable siRNA-containing NPs without and with the addition of 5-nPBA-PEGm. Five formulations, (i) cMAP with 5-nPBA-PEGm, (ii) cMAP-PEG copolymer both (a) with and (b) without 5-nPBA-PEGm, and (iii) mPEG-cMAP-PEGm triblock polymer both (a) with and (b) without 5-nPBA-PEGm, are used to produce NPs in the 30-40 nm size range, and their circulation times are evaluated in mice using tail vein injections. The mPEG-cMAP-PEGm triblock polymer provides the siRNA-containing NP with the longest circulation time (5-10% of the formulation remains in circulation at 60 min postdosing), even when a portion of the excess cationic components used in the formulation is filtered away prior to injection. A NP formulation using the mPEG-cMAP-PEGm triblock polymer that is free of excess components could contain as much as ca. 30 wt % siRNA.

Lack of in vivo antibody dependent cellular cytotoxicity with antibody containing gold nanoparticles.

Antibody-dependent cellular cytotoxicity (ADCC) is a cytolytic mechanism that can elicit in vivo antitumor effects and can play a significant role in the efficacy of antibody treatments for cancer. Here, we prepared cetuximab, panitumumab, and rituximab containing gold nanoparticles and investigated their ability to produce an ADCC effect in vivo. Cetuximab treatment of EGFR-expressing H1975 tumor xenografts showed significant tumor regression due to the ADCC activity of the antibody in vivo, while the control antibody, panitumumab, did not. However, all three antibody containing nanoparticles are not able to suppress tumor growth in the same in vivo mouse model. The antibody containing nanoparticles localized in the tumors and did not suppress the immune function of the animals, so the lack of tumor growth suppression of the cetuximab containing nanoparticle suggests that immobilizing antibodies onto a nanoparticle significantly decreases the ability of the antibody to promote an ADCC response.

Disparities in Sporadic Vestibular Schwannoma Initial Presentation Between a Public Safety Net Hospital and Tertiary Academic Medical Center at the Same Zip Code 2010 to 2020.

INTRODUCTION: Treatment of vestibular schwannoma (VS) has been extensively studied, but a gap in knowledge exists demonstrating how racial and socioeconomic status influence VS presentation. Our institution has a unique setting with a public safety net hospital (PSNH) and tertiary academic medical center (TAMC) in the same zip code, which we study to evaluate initial VS presentation disparities in patient populations presenting to these hospital settings. METHODS: Retrospective chart review was performed of all adult patients (n = 531) presenting 2010 to 2020 for initial VS evaluation at TAMC (n = 462) and PSNH (n = 69). Ethnicity, insurance, maximum tumor size, audiometry, initial treatment recommendation, treatment received, and follow up were recorded and statistical analysis performed to determine differences. RESULTS: Average age at diagnosis (51.7 ± 13.6 TAMC vs 52.3 ± 12.4 PSNH) and gender (58.4% TAMC vs 52.2% PSNH female) were similar. Patients' insurance (TAMC 75.9% privately insured vs PSNH 82% Medicaid) and racial/ethnic profiles (TAMC 67.7% White and 10.0% Hispanic/Latinx, vs PSNH 4.8% White but 59.7% Hispanic/Latinx) were significantly different. Tumor size was larger at PSNH (20.2 ± 13.3 mm) than TAMC (16.6 ± 10.0 mm). Hearing was more impaired at PSNH than TAMC (mean pure tone average 58.3 dB vs 43.9 dB, word recognition scores 52.3% vs 68.2%, respectively). Initial treatment recommendations and treatment received may include more than 1 modality. TAMC patients were offered 66.7% surgery, 31.2% observation, and 5.2% radiation, while PSNH patients offered 50.7% observation, 49.3% surgery, and 8.7% radiation. TAMC patients received 62.9% surgery, 32.5% observation, and 5.3% radiation, while PSNH patients received 36.2% surgery, 59.4% observation, and 14.5% radiation. Follow up and treatment at the same facility was not significantly different between hospitals. CONCLUSIONS: Hearing was worse and tumor size larger in patients presenting to PSNH. Despite worse hearing status and larger tumor size, the majority of PSNH patients were initially offered observation, compared to TAMC where most patients were initially offered surgery.

Idiopathic Intracranial Hypertension: Implications for the Otolaryngologist.

Idiopathic intracranial hypertension (IIH) is a triad of headaches, visual changes, and papilledema in the absence of a secondary cause for elevated intracranial pressure. There is an association with obesity, and the incidence is rising in parallel with the obesity epidemic. Sometimes these patients present to an otolaryngologist with complaints like tinnitus, dizziness, hearing loss, and otorrhea or rhinorrhea from cerebrospinal fluid leak. IIH diagnosis in conjunction with neurology and ophthalmology, including neuroimaging and lumbar puncture with opening pressure, is key to managing of this condition. Otolaryngologists should recognize IIH as a possible diagnosis and initiate appropriate referrals and treatment.

Congenital duplicated incus in the mastoid cavity.

Many congenital ossicular chain malformations exist, usually involving ossicular deformities, fixation, absence, or discontinuity. Duplication of ossicles has not been reported, much less a duplicated ossicle located in the mastoid. We present a case of a patient who had a duplicated incus in the mastoid antrum.

Trends in Hearing Protection Use With Occupational Noise Exposure in the United States 1999 to 2016.

OBJECTIVE: Determine hearing protection use in relation to occupational noise exposure, tinnitus, and audiometry-measured hearing loss in the United States from 1999 to 2016. STUDY DESIGN: Cross-sectional study utilizing US National Health and Nutritional Examination Survey (NHANES) 1999 to 2016 with occupation, reported occupational noise exposure, hearing protection use, tinnitus, and audiometry-measured hearing loss data. Subgroup analysis divided data into two cohorts early 2000s and 2010s. SETTING: Population-based study using NHANES database capturing representative sample of US population. PARTICIPANTS: Individuals with complete data 1999 to 2004 (n = 10,347) and 2011 to 2012 with 2015 to 2016 (n = 9,383). INTERVENTIONS: Participants self-reported occupational noise exposure lasting more than 4 h/d for more than 3 months. Self-reported hearing protective device uses and tinnitus frequency. Audiometric hearing loss objectively measured. MAIN OUTCOME MEASURES: Hearing protection use. Secondary measures included self-reported bothersome tinnitus and audiometrically measured hearing loss. RESULTS: Across occupations, reported occupational noise exposure was higher in 2010s [32%, 95% CI: 29.6-34.6%] than 2000s [12.5%, 95% CI: 11.2-13.9%], while hearing protection use remained low in 2000s [41.3%, 95% CI: 37.8-44.8%] and 2010s [32.8%, 95% CI: 29.8-35.8%]. Less hearing protection use was associated with absence of bothersome tinnitus. Factors associated with increased hearing protection use were younger age, male sex, college education or higher, and white race in a multivariate model. CONCLUSIONS: Reported occupational noise exposure appeared to increase from 2000s to 2010s yet hearing protection use remained stable at low use rate. As noise exposure is a major risk factor for hearing loss, significant education and reinforcement of appropriate hearing protection use for workplace noise exposures is necessary to preserve workers' hearing.

Potent kinetic stabilizers that prevent transthyretin-mediated cardiomyocyte proteotoxicity.

A valine-to-isoleucine mutation at position 122 of the serum protein transthyretin (TTR), found in 3 to 4% of African Americans, alters its stability, leading to amyloidogenesis and cardiomyopathy. In addition, 10 to 15% of individuals older than 65 years develop senile systemic amyloidosis and cardiac TTR deposits because of wild-type TTR amyloidogenesis. Although several drugs are in development, no approved therapies for TTR amyloid cardiomyopathy are yet available, so the identification of additional compounds that prevent amyloid-mediated cardiotoxicity is needed. To this aim, we developed a fluorescence polarization-based high-throughput screen and used it to identify several new chemical scaffolds that target TTR. These compounds were potent kinetic stabilizers of TTR and prevented TTR tetramer dissociation, partial unfolding, and aggregation of both wild type and the most common cardiomyopathy-associated TTR mutant, V122I-TTR. High-resolution co-crystal structures and characterization of the binding energetics revealed how these diverse structures bound to tetrameric TTR. These compounds effectively inhibited the proteotoxicity of V122I-TTR toward human cardiomyocytes. Several of these ligands stabilized TTR in human serum more effectively than diflunisal, which is a well-studied inhibitor of TTR aggregation, and may be promising leads for the treatment or prevention of TTR-mediated cardiomyopathy.