Faculty Bibliography

Oxytocin is a small, nine amino acid peptide synthesized and released mostly in the brain. It was discovered first as a hormone that facilitates labor and lactation but has since attracted interest for having important roles in social bonding. Although sometimes informally called a 'love hormone', this is erroneous and does not accurately reflect the biological action of oxytocin across different contexts. Here we provide an overview of the organization of the oxytocin system, which subserves different biological functions that ultimately coordinate physiological and behavioral states supporting reproductive success (Figure 1).

BACKGROUND/UNASSIGNED:A central vestibular neural mechanism known as velocity storage may be inappropriately conditioned in mal de débarquement syndrome (MdDS), a rare chronic vestibular disorder with a continuous false sensation of self-motion described as non-spinning vertigo. Visual-vestibular therapy approaches designed to recondition the three-dimensional properties of velocity storage have yielded much clinical success, but not without limitations. An alternative therapeutic approach, designed to attenuate the contribution of malfunctioning velocity storage in higher-order neural processing, has also yielded positive results, but at a lower success rate. We sought a possible explanation for the latter shortcoming using a mathematical model. METHODS/UNASSIGNED:The three-dimensional orientation properties of velocity storage can be modeled as a dynamical system using a 3 × 3 system matrix. For normal upright, the system matrix is diagonal, with its eigenvectors aligning with the head-fixed roll, pitch, and yaw axes, and the yaw eigenvector with gravity. A pull sensation of MdDS has been expressed with a system matrix with off-diagonal elements representing cross-axis coupling and interpreted as a misalignment between the yaw eigenvector and the head vertical. We manipulated the velocity storage's yaw time constant and output weight. RESULTS/UNASSIGNED:The model predicted that attenuating the velocity storage contribution could exaggerate the pull sensation. CONCLUSION/UNASSIGNED:The present model-based exploration points to a possible weakness in the MdDS treatment approach focused on velocity storage attenuation, while likely beneficial otherwise. When a pulling sensation is present, the treatment protocol may need to be supplemented with another approach that specifically counters this problem, such as optokinetic stimulation.

OBJECTIVE/UNASSIGNED:We sought to consolidate the anatomical findings from radiologic research and prior surgical literature to develop a stepwise surgical approach utilizing cadaveric specimens which can serve to improve the accuracy and scalability of surgical apical cochleostomies in the future. METHODS/UNASSIGNED:Cadaveric temporal bone dissections, with subsequent image documentation and distance measurements to confirm surgical accuracy. RESULTS/UNASSIGNED:All four temporal bones (100%) that were drilled utilizing the newly developed surgical approach had an accurately placed apical cochleostomy. No inadvertent entry into the middle turn of the cochlea occurred. There was no violation of the labyrinthine facial nerve, or carotid artery. CONCLUSIONS/UNASSIGNED:Preliminary findings are promising for the described steps to achieve a substantial improvement in apical cochleostomy accuracy, with reduced trauma compared to historically taught techniques.

We conducted an umbrella review to synthesize the evidence on the diagnostic performance of liquid biopsy tests for detection of head and neck squamous cell carcinoma (HNSCC). Systematic reviews (SRs) were searched in Medline, Embase, and Google Scholar through December 6, 2023. The Joanna Briggs Institute Critical Appraisal Tool for Systematic Reviews was used to assess methodological quality. Two independent reviewers extracted data. We examined the pooled sensitivity and specificity of biomarker classes. We also statistically pooled sensitivity and specificity of individual biomarkers for oral SCC in cases where meta-analysis was not yet published, since most HNSCC occurs in the oral cavity. Performance was also assessed by specimen type (saliva, serum, plasma, and whole blood). Thirty-one SRs met inclusion criteria and 21 included meta-analyses on transcriptomic, proteomic, genomic, or metabolomic biomarkers. Overall methodologic quality was moderate to high. Primary study overlap was ≥ 15 % in 9.3 % of SR pairwise comparisons. MicroRNA (miRNA) was the biomarker class represented in the most SRs (n = 19) and individual studies (n = 106). Among these, the highest sensitivity was 77 % (95 % CI, 68-84 %), observed in miRNA-21. Hypermethylated DNA was the biomarker class with the highest pooled sensitivity (86 %; 95 % CI, 60-96 %) and specificity (92 %; 95 % CI, 80-97 %) overall, and with superior performance when used in panels compared to individual markers. In studies focused on OSCC detection, no other biomarker class or fluid type demonstrated superior performance over others. In future clinical studies, panels including hypermethylated DNA merit more rigorous evaluation to establish high specificity in addition to sufficient sensitivity.

By improving the delivery and tumor retention of chemotherapeutics, nanomedicines hold potential for cancer treatment. The usefulness of nanoparticle (NP)-encapsulated analgesics for the cancer pain treatment is comparatively unexplored. We investigated whether NPs encapsulating olcegepant (OCP), an antagonist of the calcitonin receptor-like receptor (CLR) for the calcitonin gene-related peptide (CGRP), effectively relieved oral cancer pain in mice. Because persistent endosomal CLR signaling in Schwann cells mediates craniofacial pain, we reasoned that the predisposition of NPs to accumulate in endosomes could be leveraged to effectively relieve oral cancer pain. By expressing biosensors for activated CLR, Gα proteins and β-arrestins in HEK293T and Schwann cells, we found that CGRP activates CLR signaling first at the plasma membrane and then in early, late and recycling endosomes and the cis- and trans-Golgi apparatus. We synthesized biocompatible NPs encapsulating OCP and fluorophores by integrating hydrophobic ion pairing nanoformulation with Flash NanoPrecipitation. NPs slowly released OCP and accumulated in early endosomes, leading to sustained inhibition of endosomal CLR signaling in HEK293T and Schwann cells. Oral cancers were established in mice, which led to heightened pain-like responses. After intra-tumoral injection, NPs were retained in tumors for at least one week. OCP-loaded NPs almost completely reversed allodynia and hyperalgesia for a prolonged period, whereas unencapsulated OCP had small and transient effects. The NP accumulation in endosomal sites of pain signaling, the sustained release of antagonist, and the retention of NPs in tumors explain their beneficial actions. Thus, NP-encapsulation holds promise for the relief of painful cancers that are inadequately treated by opioids.

BACKGROUND/UNASSIGNED:While traditional risk stratification for thyroid cancer primarily focused on tumor pathology, molecular profiling is increasingly recognized for its clinical relevance. There are limited data on tumors with three or more mutations, especially when presenting with non-malignant cytology. This study aims to evaluate the clinical behavior of cytologically non-malignant thyroid nodules with three or more potent oncogenic mutations. METHODS/UNASSIGNED:Electronic medical records of patients at our institution with thyroid nodules who underwent molecular testing were reviewed to identify cases with cytologically benign or indeterminate thyroid nodules that harbored three or more oncogenic mutations. Clinical, cytological, and molecular data were analyzed to assess tumor behavior. RESULTS/UNASSIGNED:Four of six cases were histologically malignant at index surgery. One histologically benign case developed distant metastases 7 years later. Retrospective analysis of the two histologically benign cases and the one case with low-risk histology demonstrated significant intratumoral heterogeneity. The benign case that developed distant metastases was found to have an area of intratumoral heterogeneity whose genetic profile matched the metastases. CONCLUSIONS/UNASSIGNED:Despite bland cytological and ultrasonographic features, these tumors exhibited aggressive behavior. The molecular profile of thyroid cancers should be considered when determining treatment, especially in cases with multiple high-risk mutations, as they may behave more aggressively than predicted by cytology or imaging alone.

The current management of vestibular schwannomas (VS) includes observation, microsurgery, and stereotactic radiosurgery (SRS) or radiotherapy. Both microsurgery (MS) and irradiation have the potential for treatment failures. For microsurgical failures, options include observation, revision surgery, and SRS. SRS is most commonly used, as it carries a low risk of adverse events. Salvage MS following previous MS is reserved for specific cases and is often surgically challenging. For radiosurgical failures, both salvage MS and repeat SRS may be used. Salvage MS following SRS also tends to be challenging, although excellent facial nerve outcomes are achievable. Furthermore, repeat SRS is an emerging concept and should be considered in small tumors that are growing but are asymptomatic. This chapter is aimed at reviewing an approach to failure of primary interventions for vestibular schwannomas, with an emphasis on the time interval between modalities, tumor control rates, functional outcomes, and complications.

Gamma knife stereotactic radiosurgery is one of the most common procedures performed to manage patients with vestibular schwannoma. With a history that spans over 40 years, there has been continued evolution in radiosurgery technique and understanding of outcomes. The goal has always been to achieve long-term inactivation of tumor growth, commonly with tumor volumetric regression, and preservation of neurologic function. Challenges remain particularly pertaining to hearing preservation and other related symptoms such as those related to balance and tinnitus. Current discussions span a variety of topics including the importance of cochlear dose, the timing of the radiosurgery intervention as opposed to initial observation, the interpretation of imaging changes after radiosurgery, and the value of hearing augmentation strategies.

Although many internalized G protein-coupled receptors (GPCRs) continue to signal, the mechanisms and outcomes of intracellular GPCR signaling are uncertain due to the challenges of measuring organelle-specific signals and of selectively antagonizing receptors in intracellular compartments. Herein, genetically encoded biosensors targeted to the plasma membrane and early endosomes were used to analyze compartmentalized signaling of protease-activated receptor 2 (PAR₂); the propensity of nanoparticles (NPs) to accumulate in endosomes was leveraged to preferentially antagonize intracellular PAR₂ signaling of pain. PAR₂ agonists evoked sustained activation of PAR₂, Gαq, and β-arrestin-1 in early endosomes and activated extracellular signal regulated kinase (ERK) in the cytosol and nucleus, measured with targeted biosensors. Fluorescent dendrimer and core-shell polymeric NPs accumulated in endosomes of HEK293T cells, colonic epithelial cells, and nociceptors, detected by confocal microscopy. NPs efficiently encapsulated and slowly released AZ3451, a negative allosteric PAR₂ modulator. NP-encapsulated AZ3451, but not unencapsulated AZ3451, rapidly and completely reversed PAR₂, Gαq, and β-arrestin-1 activation in early endosomes and ERK activation in the cytosol and nucleus. When administered into the mouse colon lumen, fluorescent dendrimer NPs accumulated in endosomes of colonocytes and polymeric NPs accumulated in neurons, sites of PAR₂ expression. Both NP formulations of AZ3451, but not unencapsulated AZ3451, caused long-lasting analgesia and normalized aberrant behavior in preclinical models of inflammatory bowel disease. These results provide evidence that PAR₂ endosomal signaling mediates pain and that nanomedicines that antagonize PAR₂ in endosomes effectively relieve pain. NP-mediated delivery may improve the efficacy of other GPCR antagonists for treatment of diverse diseases.