Faculty Bibliography

Virtual reality allows for testing of multisensory integration for balance using portable Head Mounted Displays (HMDs). HMDs provide head kinematics data while showing a moving scene when participants are not. Are HMDs useful to investigate postural control? We used an HMD to investigate postural sway and head kinematics changes in response to auditory and visual perturbations and whether this response varies by context. We tested 25 healthy adults, and a small sample of people with diverse monaural hearing (n = 7), or unilateral vestibular dysfunction (n = 7). Participants stood naturally on a stable force-plate and looked at 2 environments via the Oculus Rift (abstract "stars;" busy "street") with 3 visual and auditory levels (static, "low," "high"). We quantified medio-lateral (ML) and anterior-posterior (AP) postural sway path from the center-of-pressure data and ML, AP, pitch, yaw and roll head path from the headset. We found no difference between the different combinations of "low" and "high" visuals and sounds. We then combined all perturbations data into "dynamic" and compared it to the static level. The increase in path between "static" and "dynamic" was significantly larger in the city environment for: Postural sway ML, Head ML, AP, pitch and roll. The majority of the vestibular group moved more than controls, particularly around the head, when the scenes, especially the city, were dynamic. Several patients with monaural hearing performed similar to controls whereas others, particularly older participants, performed worse. In conclusion, responses to sensory perturbations are magnified around the head. Significant differences in performance between environments support the importance of context in sensory integration. Future studies should further investigate the sensitivity of head kinematics to diagnose vestibular disorders and the implications of aging with hearing loss to postural control. Balance assessment and rehabilitation should be conducted in different environmental contexts.

The auditory system is sensitive to stimulus regularities such as frequently occurring sounds and sound combinations. Evidence of regularity detection can be seen in how neurons across the auditory network, from brainstem to cortex, respond to the statistical properties of the soundscape, and in the rapid learning of recurring patterns in their environment by children and adults. Although rapid auditory learning is presumed to involve functional changes to the auditory network, the chronology and directionality of changes are not well understood. To study the mechanisms by which this learning occurs, auditory brainstem and cortical activity was simultaneously recorded via electroencephalogram (EEG) while young adults listened to novel sound streams containing recurring patterns. Neurophysiological responses were compared between easier and harder learning conditions. Collectively, the behavioral and neurophysiological findings suggest that cortical and subcortical structures each provide distinct contributions to auditory pattern learning, but that cortical sensitivity to stimulus patterns likely precedes subcortical sensitivity.

Oral squamous cell carcinoma (SCC) pain is more prevalent and severe than pain generated by any other form of cancer. We previously showed that protease-activated receptor-2 (PAR₂) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR₂. We report here a role for cathepsin S in PAR₂-dependent cancer pain. We report that cathepsin S was more active in human oral SCC than matched normal tissue, and in an orthotopic xenograft tongue cancer model than normal tongue. The multiplex immunolocalization of cathepsin S in human oral cancers suggests that carcinoma and macrophages generate cathepsin S in the oral cancer microenvironment. After cheek or paw injection, cathepsin S evoked nociception in wild-type mice but not in mice lacking PAR₂ in Na_v1.8-positive neurons (Par₂Na_v1.8), nor in mice treated with LY3000328 or an endogenous cathepsin S inhibitor (cystatin C). The human oral SCC cell line (HSC-3) with homozygous deletion of the gene for cathepsin S (CTSS) with CRISPR/Cas9 provoked significantly less mechanical allodynia and thermal hyperalgesia, as did those treated with LY3000328, compared to the control cancer mice. Our results indicate that cathepsin S is activated in oral SCC, and that cathepsin S contributes to cancer pain through PAR₂ on neurons.

In contrast to adults, meningiomas are uncommon tumors in childhood and adolescence. Whether adult and pediatric meningiomas differ on a molecular level is unclear. Here we report detailed genomic analyses of 37 pediatric meningiomas by sequencing and DNA methylation profiling. Histologically, the series was dominated by meningioma subtypes with aggressive behavior, with 70% of patients suffering from WHO grade II or III meningiomas. The most frequent cytogenetic aberrations were loss of chromosomes 22 (23/37 [62%]), 1 (9/37 [24%]), 18 (7/37 [19%]), and 14 (5/37 [14%]). Tumors with NF2 alterations exhibited overall increased chromosomal instability. Unsupervised clustering of DNA methylation profiles revealed separation into three groups: designated group 1 composed of clear cell and papillary meningiomas, whereas group 2A comprised predominantly atypical meningiomas and group 2B enriched for rare high-grade subtypes (rhabdoid, chordoid). Meningiomas from NF2 patients clustered exclusively within groups 1 and 2A. When compared with a dataset of 105 adult meningiomas, the pediatric meningiomas largely grouped separately. Targeted panel DNA sequencing of 34 tumors revealed frequent NF2 alterations, while other typical alterations found in adult non-NF2 tumors were absent. These data demonstrate that pediatric meningiomas are characterized by molecular features distinct from adult tumors.

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

Metastatic melanoma may be included in the differential diagnosis of hyoid masses in patients with a history of melanoma. Hyoid resection is well tolerated and of diagnostic and therapeutic benefit in patients with tumors metastatic to the hyoid bone.

The application of exercise science training knowledge has been of growing interest to voice professionals. This tutorial, derived from the authors' invited presentations from the "Exercise and the Voice" Special Session at the 2018 Voice Foundation Symposium, proposes a foundational theoretical structure based in exercise science, clarifies the wide range of variables that may influence voice training, and summarizes our present understanding of voice physiology from the perspective of muscle training. The body of literature on voice exercise was then analyzed from the perspective of this framework, identifying what we currently know and what we still have yet to learn.

Most head and neck paragangliomas (PGLs) are biochemically silent and often present with recurrence and metastases in association with hereditary syndromes. Whole-body functional imaging is increasingly used to detect tumor extent and guide treatment planning of PGLs. [68Ga]-DOTATATE, which targets somatostatin receptor 2 (SSTR2) overexpression, has emerged as a sensitive functional imaging modality in PGLs. We present a patient with metastatic glomus caroticum PGL in whom [68Ga]-DOTATATE PET/MRI provided a more accurate characterization of metastatic extent, as compared to gadolinium-enhanced MRI of the neck and whole body [18F]-FDG PET/CT. We then review the current literature and discuss the imaging implications of [68Ga]-DOTATATE PET/MRI in PGLs.

PURPOSE/OBJECTIVE:Artificial intelligence (AI) is about to touch every aspect of radiation therapy, from consultation to treatment planning, quality assurance, therapy delivery, and outcomes modeling. There is an urgent need to train radiation oncologists and medical physicists in data science to help shepherd AI solutions into clinical practice. Poorly trained personnel may do more harm than good when attempting to apply rapidly developing and complex technologies. As the amount of AI research expands in our field, the radiation oncology community needs to discuss how to educate future generations in this area. METHODS AND MATERIALS/METHODS:The National Cancer Institute (NCI) Workshop on AI in Radiation Oncology (Shady Grove, MD, April 4-5, 2019) was the first of 2 data science workshops in radiation oncology hosted by the NCI in 2019. During this workshop, the Training and Education Working Group was formed by volunteers among the invited attendees. Its members represent radiation oncology, medical physics, radiology, computer science, industry, and the NCI. RESULTS:In this perspective article written by members of the Training and Education Working Group, we provide and discuss action points relevant for future trainees interested in radiation oncology AI: (1) creating AI awareness and responsible conduct; (2) implementing a practical didactic curriculum; (3) creating a publicly available database of training resources; and (4) accelerating learning and funding opportunities. CONCLUSION/CONCLUSIONS:Together, these action points can facilitate the translation of AI into clinical practice.

Establishing a causal link between neural function and behavioral output has remained a challenging problem. Commonly used perturbation techniques enable unprecedented control over intrinsic activity patterns and can effectively identify crucial circuit elements important for specific behaviors. However, these approaches may severely disrupt activity, precluding an investigation into the behavioral relevance of moment-to-moment neural dynamics within a specified brain region. Here we discuss the application of mild focal cooling to slow down intrinsic neural circuit activity while preserving its overall structure. Using network modeling and examples from multiple species, we highlight the power and versatility of focal cooling for understanding how neural dynamics control behavior and argue for its wider adoption within the systems neuroscience community.