2017 Stanford OHNS Basic and Translational Research Report

Overview

Last year was another highly successful year for the Research Division. It is very obvious that our department’s research scope has grown far beyond the initial focus on inner ear regeneration. The latitude of projects cover:  surgical simulation, improving audiologic training for patients, immune response to cancer, advanced imaging, African elephant communication, novel non-ototoxic aminoglycoside antibiotics, stem cells, hair cell regeneration, voice disorders, hair cell mechano-transduction, synaptic and neural coding of sound information, as well as the impact of tobacco advertising – just to name a few.  Clinical work has been focusing quite a bit on adapting principles of precision medicine, where patient-specific information is more and more taken into account.  Of course, the core of the basic research group remains the goal of finding a cure for hearing loss and we are happy to report that fundraising for the Stanford Initiative to Cure Hearing Loss (hearinglosscure.stanford.edu) has been at the highest level since we started the initiative a couple of years ago.  Funding through grants from federal and other entities continued to grow for the 11th year in a row.  The number of grants towards research stands at a record number of 68.  Productivity remains high and the quality of work has been recognized by many of our peers as outstandingly strong.

All faculty members who maintain an active endeavors have provided updates on their work and these updates are provided in the following pages.  This report highlights basic and translational research in the department.  Departmental faculty also contribute a sizable volume of clinically focused research.

Nikolas Blevins

CardinalSim – Development of a Virtual Surgical Rehearsal Platform

The CardinalSim research team, led by Nikolas Blevins and Kenneth Salisbury, continues to develop a platform to enable surgeons to rehearse complex cranial base surgical procedures based on preoperative anatomic imaging data.  The primary hypothesis driving this project is that surgical outcomes will improve if surgeons are able to explore relevant anatomic data in an intuitive and surgically-relevant manner, prior to undertaking actual surgery.  Clinicians currently have access to a wealth of preoperative imaging data (including both CT and MRI data) which are routinely examined only across-sectional abstractions of the complex 3-dimensional anatomic configurations they represent.  The “CardinalSim” platform (http://med.stanford.edu/cardinalsim.html) addresses this, by allowing surgeons to load interact with clinical imaging data using haptic (touch) interfaces and stereoscopic displays (1).  By exploring relevant anatomic relationships in a safe environment, the surgeon can be better prepared for otherwise unexpected challenges, thereby potentially minimizing risks.

Over the last year, our team has confirmed that surgical trainees using the workstation are capable of replicating key steps in a variety of temporal bone surgical procedures (2).  The confirmation of our ability to accurately produce and display the surgically-relevant details that guide the course of a procedure is a critical step in validating our approach.  Also this year, we completed a study demonstrating that the use of the simulation workstation in conjunction with actual anatomic dissections in a surgical laboratory could increase trainee confidence in performing experience-appropriate challenging segments of otologic surgery (3).  This confirms that anatomy-specific rehearsal in our virtual environment can augment preparation for actual dissections.

Plans for the coming year include the facilitation of collaborative rehearsal through a shared database of cases, the incorporation of physics-based sound and deformable tissues into the virtual environment, and the development of effective methods to optimally displaythe insights from rehearsalwithin the operation room.

 

  • Chan S, Li P, Locketz G, Salisbury K, Blevins NH. (2016). High-fidelity haptic and visual rendering for patient-specific simulation of temporal bone surgery. Computer Aided Surgery.DOI: 10.1080/24699322.2016.1189966
  •  Locketz GD, Lui JT, Chan, SK, Salisbury K, Dort JC, Youngblood P, Blevins NH. (2016). Replicating surgical procedures in patient specific virtual reality; presented at AAO/HNS Annual Meeting
  •  Locketz GD, Lui JT, Chan, SK, Salisbury K, Dort JC, Youngblood P, Blevins NH.  (Accepted 2016). Anatomy-specific virtual reality simulation in temporal bone dissection: impact on surgeon confidence and dissection performance. Otolaryngol Head Neck Surg.

 

Electrophysiology and the Classification of Auditory Stimuli

Our auditory electrophysiology research group has undertaken an investigating of non-invasive methods of assessing the efficacy of hearing restoration. We are using newclassification techniques of EEG data to determine if an individual with normal or altered hearing is able to differentiate between auditory stimuli. This approach may provide insights into the optimal means of presenting hearing signals to specific individuals, optimized for both their inner ears as well as their central auditory processing capacity. It is known that patients with hearing loss can respond quite differently to auditory signals. This is particularly the case for cochlear implant recipients in whom normal transduction of signals by the cochlea has been replaced by relatively few electrical contacts. These individuals oftenshow little ability to express the character of their experience – which is especially true for young children and those who have never experienced hearing. It is also clear that over time, such individuals can adapt and change in their response to stimuli, often being able to extract considerably more from the same signals.  We hypothesize that a method to extract electrophysiologic data from EEG signals will provide insights into how to best present signals to a cochlear implant user to provide prognostic data and also optimize ultimate outcomes. Our preliminary data establishing these techniques in normal hearing individuals has been quite promising, and will be presented at the next meeting of the Association of Research in Otolaryngology.

 

Fitzgerald M, Losorelli S, Muscacchia G, Kaneshiro B, Blevins NH. Classification of auditory stimuli using event-related potentials. Accepted for presentation at ARO, 2017.

Alan G. Cheng

The Cheng laboratory has made important discoveries on several fronts in the past year. In the regeneration program, a new direction of our lab is to characterize the cells surrounding hair cells (the supporting cells). Since supporting cell loss leading to hair cell loss is the major cause of congenital hearing loss, we have been studying whether supporting cells can regenerate and how their loss causes secondary hair cell loss and eventually hearing loss. Moreover, we have been following up on our previous work that the immature mouse cochlea harbors progenitors (also supporting cells) that naturally regenerate hair cells after damage. Ongoing efforts focus on defining mechanisms that initiate or enhance this innate regenerative process. 

In parallel, we continue to explore whether hair cell regeneration leads to a functional recovery in mammals. To better understand this process, we have been studying one of inner ear balance organs, the utricle, where a modest level of regeneration occurs. By establishing a time course of hair cell loss and subsequent regeneration and a whole animal vestibular function test, we have found significant differences between the young and mature utricle in terms of the degree and mechanisms of regeneration and also the degree of functional recovery. In the near future, we will be able to precisely describe the anatomy and function of a regenerating mammalian sensory organ, such that we can manipulate the degree of regeneration and assess how that affects functional recovery.

Our research program on cochlear development has been focusing one key signaling pathway, Wnt signaling, and how it regulates hair cell development. The complexity of this pathway lends itself to a step-by-step interrogation of individual components of the pathway. Thus far, we have found that this pathway affects both cell fate decision, maturation as well as organization of the developing cochlea, thus providing important insights into how to manipulate this pathway to promote regeneration.

Lastly, our group has been collaborating with Tony Ricci in developing novel non-ototoxic antibiotics. Using some of the latest technology in physics, we have visualized how our antibiotics interact with bacteria at the molecular level. This is critical information that will help guide us design additional versions of antibiotics that can prevent hearing loss.

Another mission of our group is foster the future generation of researchers to find a cure for hearing loss. We are extremely fortunate to have a talented of young, energetic and motivated scientists who work collaboratively. It has been a stellar year for them to have been awarded 2 grants from the NIH (Zahra Sayyid MSTP student, Tian Wang MD PhD research scientist), and 2 international grants from Australia (Patrick Atkinson PhD postdoctoral fellow) and European Union (Mary O’Sullivan PhD postdoctoral fellow).

 

Jan TA, Jansson L, Atkinson PJ, Wang T, Cheng AG. (2016). Profiling specific inner ear cell types using cell sorting techniques. Methods Mol Biol 1427:431-45. doi: 10.1007/978-1-4939-3615-1_23. PMCID: pending

Elizabeth Erickson-Direnzo

Voice disorders affect millions of people in the United States annually. The Laryngeal Research Laboratory is an interdisciplinary research group that was established by Dr. Elizabeth DiRenzo, PhD, CCC-SLP in 2015. The Laryngeal Research Laboratory uses techniques from the basic sciences and human clinical sciences to improve the prevention and treatment of voice disorders. To truly improve voice disorder management, the cellular and molecular underpinnings of laryngeal disease and the vocal fold response to potentially hazardous external stresses must be understood. Specifically, we investigate how external stresses such as inhaled pollutants, viruses, bacteria, and radiation compromise the structure and function of the vocal fold mucosa and how these changes may influence voice production. We use diverse models and methodologies including animal models and cell cultures. We also collaborate with surgeons within the Division of Laryngology to obtain human tissue samples from patients with a wide-variety of voice disorders. Of note, this year we published on how radiation affects the structure and function of the cells that form the vocal fold mucosa (Erickson-DiRenzo, Annals of Otology, Rhinology, & Laryngology, 2016).

In the coming year, we are embarking on a new line of research aimed specifically at elucidating the etiologyand mechanism of action of tobacco product-induced laryngeal disease. Specifically, we are developing a novel mouse model of cigarette smoke and electronic (e)-cigarette vapor-induced inflammation that can be used to study the pathophysiological changes that occur in the larynx of human tobacco users. At the same time, we are also performing a multidimensional study of vocal function in users of conventional cigarettes and e-cigarettes. Such investigations will be the first to systematically examine the effect of e-cigarettes on the laryngeal mucosa and vocal function.

Finally, we also study clinical and quality of life outcomes in patients with voice disorders undergoing a variety of surgical or behavioral interventions. We are currently collaborating with researchers in the Departments of Neurosurgery and Neurology to investigate the effectiveness of deep brain stimulation (DBS) for the treatment of essential vocal tremor. Vocal tremor is a common and often debilitating voice disorder with no known cure and limited effective treatments. In 2016, Dr. DiRenzo was the Principal Investigator on a grant from the American Speech-Language-Hearing Foundation to pursue this line of research and we will be publishing our initial findings in the coming year. Results will provide a necessary foundation for future studies that seek to optimize DBS for the treatment of vocal tremor and have the potential to alter treatment paradigms for these difficult to serve patients. Overall, we look forward to continuing expandresearch group, disseminating findings, and utilizing research discoveries to develop novel new interventions for voice disorders. 

Matthew Fitzgerald

In the Division of Audiology, our research efforts took three forms.   First, we continued to investigate novel training procedures to facilitate learning and adaptation in individuals with hearing loss.   We have demonstrated that individuals with hearing loss show different patterns of learning than individuals with normal hearing.  This suggests that customized training programs may need to be developed for individuals with cochlear implants or hearing aids. 

In our second line of research, we have laid the groundwork for a fundamental change in the audiologic test battery; making speech in noise the default clinical test of speech perception rather than word-recognition in quiet.  We have collected data on over 1500 individuals which reveal that in most instances, speech in noise testing can replace word-recognition in quiet, and provide clear clinical guidelines for when to perform word-recognition in quiet. 

Finally, we continue to investigate the mechanisms by which individuals with bilateral cochlear implants fuse information provided by each device.  We have shown that some individuals are sensitive to mismatches in electrode insertion depth, while others are not.  We have also demonstrated that self-selection of frequency tables has the potential to overcome any deficits in performance caused by between-ear mismatches in stimulation.  Taken together, these lines of research have the potential to directly impact clinical practice, and to facilitate improvements in patient performance in the future. 

Fitzgerald, M.B., Aaron, K.A., Tan, C-T., Glassman, E.K., and Svirsky, M.A.  (in press).  Self-selection of frequency tables with bilateral mismatches in an acoustic simulation of a cochlear implant. Journal of the American Academy of Audiology.

Nicolas Grillet

In 2016, the Grillet lab published three research papers in highly ranked journals, including two that conclude Dr. Grillet’s postdoctoral work. For each of them, new experiments were done at Stanford and involved members of the Grillet lab, Alix Trouillet (Postdoctoral Fellow) and Navid Zebarjadi (Research Assistant).

In the first publication, we characterized a gene responsible for deafness in a randomly mutated mouse strain. This gene, called Neuroplastin, codes for an adhesion molecule with two major splicing variants. These variants differ by the length of their extracellular domain. We showed that the shortest isoform is expressed specifically by the outer hair cells and is necessary for their function at 3 weeks of age. This work identified a new protein necessary for hair cell function in mice, and likely in humans as well.

In the second publication we demonstrated genetically that hair cells have two mechanical ionic channels: When the stereocilia bundle of hair cells is deflected in its normal direction of sensitivity, an electric current is generated. It is the initial current that codes for sound. When the stereocilia bundle is pushed in its reverse direction, no current is produced. Surprisingly, in newborn mice, once this mechanotransduction is abolished either by the rupturing of extracellular links that bridge the top of stereocilia to their taller neighbor, or by the genetic ablation of component of the sound mechanotransduction machinery, the hair cells show now an electric current when stimulated in the opposite direction. During the last five years a debate has emerged in the field about the origin of this current: Are both currents generated from the same ionic channel reconfigured to function in other directionalities or are they coming from distinct mechanosensitive channels? By studying the function the mechanosensitive channel Piezo2 that plays central role other sensory systems such as touch, we demonstrated that the “opposite” or “reverse” current requires Piezo2 while the normal current does not. Therefore, our work ends the debate and opens a new exciting question about the physiological role of this current that can be also triggered by local mechanical damage of the sensory epithelium.

In addition to these two publications, Dr. Grillet helped the research of Dr. Oghalai by providing his expertise in scanning electronic microscopy to image at nanometric resolution the stereocilia bundle of adult mice.

Next year looks very exciting for the Grillet lab as significant progress has already been made on the molecular requirement of a deafness gene. Also, Mattia Carraro joined the lab as a Postdoctoral Fellow upon graduating from the University of Toronto. Mattia is an expert in immunofluorescence staining of the entire inner ear at high resolution, as well as scanning electronic microscopy to image the blood vessels of the inner ear.

 

Wu Z*, Grillet N*, Zhao B, Cunningham C, Harkins-Perry S, Coste B, Ranade S, Zebarjadi N, Beurg M, Fettiplace R, Patapoutian A, Müller U. (2016). Mechanosensory hair cells express two molecularly distinct mechanotransduction channels. Nat Neurosci. Nov 28;* Shared first-authorship.

Zeng WZ*, Grillet N*, Dewey JB, Trouillet A, Krey JF, Barr-Gillespie PG, Oghalai JS, Müller U. (2016). Neuroplastin isoform np55 is expressed in the stereocilia of outer hair cells and required for normal outer hair cell function. J Neurosci.  36(35), 9201-16;* Shared first-authorship.

Lee HY, Raphael PD, Xia A, Kim J, Grillet N, Applegate BE, Ellerbee Bowden AK, Oghalai JS. (2016). Two-dimensional cochlear micromechanics measured in vivo demonstrate radial tuning within the mouse organ of corti. J Neurosci.  36(31), 8160-73.

Stefan Heller

2016 has been a transitional year for the Heller laboratory.  We have completed two major NIH R01 grants that mark the end of a period of research focusing on the functional assessment of a specific class of ion channels, which were once plausible candidates for playing a major role in hearing and balance.  Very encouraging was that this planned transition went quite smoothly with the successful competition for a new R01 grant that focuses on assessing the molecular mechanisms by which mouse cochlear hair cells deal with noise-induced stress.  This project is important because it can provide insights into the question why some people’s ears are more resistant to noise than others’.  It also integrates well with a human genetics project pursued by Nicolas Grillet.  We also implemented quite a lot of novel technologies with a major focus on single cells transcriptomics.  This topic is a continuation of work that started a few years ago and I anticipate that we will have several major publications coming out next year as we apply this technology to study the triggers that initiate hair cell regeneration in the newborn mouse cochlea and in adult chickens. 

We had 3 publications this year.  The major one (Ealy et al., see below) describes 4 years of work on developing a way to guide human embryonic stem cells and induced pluripotent stem cells toward an early inner ear phenotype.  The second paper is the result of a collaboration with Eri Hashino’s laboratory at the University of Indiana where we contributed tools and intellectual input to optimize the generation of sensory hair cells from mouse pluripotent stem cells.  Finally, a previous postdoc of the Heller lab, who is now heading his own laboratory in China has published work on a project that started in the inner ear but concluded in muscle cells; this project begun almost a decade ago when our lab just had moved from Boston to Palo Alto.

 

Ealy M, Ellwanger DC, Kosaric N, Stapper AP, and Heller S. (2016) Single-cell analysis delineates a trajectory toward the human early otic lineage. Proc Natl Acad Sci U S A. 113: 8508-8513.

DeJonge RE, Liu XP, Deig CR, Heller S, Koehler KR, Hashino E. (2016) Modulation of Wnt Signaling Enhances Inner Ear Organoid Development in 3D Culture. PLoS One. 11:e0162508.

Cao JM, Cheng XN, Li SQ, Heller S, Xu ZG, Shi DL. (2016) Identification of novel MYO18A interaction partners required for myoblast adhesion and muscle integrity. Sci Rep. 6:36768.

Robert Jackler

Stanford Research Into the Impact of Advertising (SRITA) is an interdisciplinary research group which Dr. Jackler established over a decade ago.  SRITA studies advertising, marketing, and promotion used by the tobacco industry to recruit and retain its customer.  Our priority is research designed to inform regulators and legislators who are considering regulation of tobacco products.

The initial priority of SRITA was to create a digital repository of tobacco advertising material to support scholarship, advocacy, legal, and regulatory activity.  As of 2016, the collection has grown to become the world’s largest repository with over 40,000 tobacco advertising images many of which are online in a searchable, meta-data rich, annotated database (tobacco.stanford.edu).  The collection spans not only cigarette/cigar/pipe/snus/chew advertisements but also e-cigarettes, antismoking campaigns, with a new marijuana section in the to launch soon.  As the historical collection is now comprehensive, recent emphasis has been acquiring contemporary tobacco advertising for the US and around the world (eg. “Be Marlboro” campaign). 

As of December 2016, the online collection (tobacco.stanford.edu) includes 22,488 tobacco, 11,802 electronic cigarette, and 1152 anti-smoking advertisements. SRITA’s YouTube channel contains 178 tobacco and 157 electronic cigarette videos. Advertising comparison pairs (756) are available such as targeting women then versus now and African American versus mainstream advertisements.  As of November 2016, the SRITA online collection has had 424,522 unique users with virtually every country in the world represented.  The entire compendium of original tobacco advertisements, spanning 1890 to 2010+ have been donated to the National Museum of American History at the Smithsonian Institution.

My current research has focused upon the marketing of electronic cigarettes with special focus upon informing regulators about the advertising and promotional activities of the rapidly growing vapor industry.  In 2016 my group has published on cessation imagery in e-cigarette advertising (AJPH), e-cigarette marketers utilizing of anti-smoking imagery (Tob Contol), exotic flavor based advertising (Tob Control) and we have papers submitted on alcohol flavored tobacco products and age gating on tobacco websites. A key collaboration is with Stanford pediatric professor Bonnie Halpern-Felsher who utilizes consumer perception methodology which compliments SRITA’s focus on content analysis.  Perception studies extend and validate assumptions made via content analysis of advertisements in the SRITA collection.

In the coming year we are studying the marketing of e-cigarette flavors. The FDA banned flavors from combustible cigarette in 2009 with the exception of menthol.  In 2016, the FDA solicited research into the impact of flavored vapor products on adult smoking cessation and youth initiation.  We are studying the youth messaging of flavored e-cigarette advertising.  We are also studying the 40 year marketing effort by the menthol brand Newport which led it to become a leading teen starter smoker brand.

 

Ramamurthi D, Gall PA, Ayoub N, Jackler RK. Leading-brand advertisement of quitting smoking benefits for e-cigarettes.  Am J Public Health. 106: 2057-2063.

Jackler RK, Ramamurthi D. Unicorns cartoons: marketing sweet & creamy e-juice to youth. tob control.   doi:10.1136/ tobaccocontrol-2016- 053206.

Jackler RK, Ramamurthi D, VanWinkle C, Bumanlag IM, Fayyaz P. Alcohol Flavored Tobacco Products: Tempting Teens to Transgress Two Adult Taboos with a Single Act.  Submitted Tobacco Control Dec 2016.

Jackler RK. (2016). Testimony by otolaryngologists in defense of tobacco companies 2009-2014. Laryngoscope 125:2722–2729.

Ramamurthi D, Fadadu RP, Jackler RK. Electronic cigarette marketers manipulate anti-tobacco advertisements to promote vaping.  Tob Control 2016; 25:720-722

Mirna Mustapha

The Mustapha laboratory published a collaborative study with Dr. Most from our department contributed to understanding the role of the classical complement pathway in recovery after facial nerve injury (Akdagli et al., 2016). We have two papers under revision. One is in PLOS Genetics describing the role of thrombospondins in afferent synapses maintenance and recovery after noise injury. A second paper is in under revision in Hearing Research describing the role of adrenergic receptors in cochlear function.

  • Akdagli, S., Williams, R., Kim H.J., Yan. Y., Mustapha, M and Most, S. Comparison of facial nerve recovery after injury in KbDb and C1q homozygous knockout mice:  A preferential role for MHC-1 over the classical complement pathway in recovery after facial nerve injury. Plastic and Reconstructive Surgery - Global Open (in press).
  • Mendus D and Mustapha M. Contribution of beta1- and beta2-adrenergic receptors to cochlear function. Under revision in Hearing Research.
  • Wangsawihardja F, Balasubbu S, Sundaresan S, Leu R, Holt AG and Mustapha M. Accelerated noise-induced hearing loss and audiogenic seizure in mice lacking thrombospondins. Under revision in PLOS Genetics.
  • Mustapha M and Avril G. Holt. (2016). Genetics of deafness: in mice and men (auditory neuropathy). Perspectives from physics, Biology, Modeling, and Medicine. Chapter 5, 99-106

Jayakar Nayak

Airway diseases occur widely due to various pathologies, but their common feature is acute airway tissue damage. Understanding the biology of airway injury (of the airway epithelial barrier) and inflammation (from an altered immune system) in airway sites is of critical importance to preventing and reversing airway tissue damage. My laboratory team has continued to make advances into understanding upper airway biology, in terms of its stem cells activities and the unique nasal immune environment in the laboratory. We have also undertaken clinical research to better understand and treat the enigmatic nasal airway disorder termed empty nose syndrome.

We are undertaking some of the world's first airway stem cell transplants using ex vivo culture systems and animal models, based on human nasal basal cells (NBCs) as naturally-occurring, abundant progenitors of the source of cell therapy. We have also undertaken an exciting collaboration with 3 other eminent Stanford researchers (Drs. Matthew Porteus, Calvin Kuo and Tushar Desai) to use our stem cell culture system as a vehicle for possibly the 1st airway stem cell therapy to treat cystic fibrosis (CF) sinusitis. 100% of CF patients develop some degree of sinusitis, and 85% of these patients have a 3-base-pair mutation in the CFTR chloride transport gene. This conserved mutation produces all of the downstream debilitating sinus and pulmonary symptoms in these patients, and would be a worthwhile target for gene therapy. Indeed, our preliminary experiments suggest that the mutated CFTR gene can be ‘edited’ and corrected in primary NBC cultures from donors using modern molecular techniques. These ‘corrected’ stem cells can then theoretically be re-placed back into the nasal cavity of the same donor in treatment for CF sinusitis. As a group, we have now collectively applied for competitive funding to advance these pilot, pre-clinical experiments, and ultimately hope to develop a viable translational cell therapy for CF patients and others with sinusitis.

We have also discovered that the human upper airway tissues have significant proportions of immune cells in the setting of inflammation - granulocytes, regulatory T cells, and now B cells. These B cells appear to carry unique immunoglobulin families and signatures compared to other immune system compartments in the body, and make the nasal upper airway an microenvironment at the junction between the innate and acquired immune systems. Using high dimensional flow cytometry, we have also discovered unexpected shifts in immune cell populations in the upper airway following steroid use. Also, in collaboration with Northwestern University, have identified high levels of immunoglobulin D (IgD) in the nasal tissues of sinusitis patients, that is not seen in the circulating blood or nasal tissues of control patients. A manuscript regarding this novel finding has just recently been submitted (please see below). Eventually we hope to harness our research findings to develop new research directions in upper airway biology, and novel therapies for treating common but debilitating sinusitis issues.                                                                                                 

Finally, in my clinical practice, our groundbreaking translational research efforts in empty nose syndrome (ENS) are becoming nationally recognized for surgical reconstruction techniques and lending improved understanding, definition and treatments for patients with the intriguing nasal disorder termed empty nose syndrome. Following routine, turbinate reduction and poor wound healing we began to see more patients with ENS from both nationally and internationally. Our group sought to be at the forefront of this area of ENS research, and began focusing on establishing the validity of a 6-question intake survey that we designed, and an office-test to assess ENS and candidacy for surgery. We are now prospectively studying our early outcomes with turbinate augmentation surgery to help ENS patients regain a more normal of nasal breathing. Our research and interest in ENS finally led to our group being interviewed and partially featured in a recent February 2016 article on the Buzzfeed.com newsfeed, which is the last citation noted below.

 

  • Rashan AR, Goshn E, Peterson A, Yang Y, Phillips M, Sahaf B, Herzenberg L, and Nayak JV. (2016) Characterization of IgE plasma cells that are elevated in the upper airway mucosa of non-atopic patients with chronic rhinosinusitis without nasal polyps (CRSsNP). Int Forum Allergy Rhinol. 6:378-84.
  • Vladar EK, Nayak JV, Milla C and Axelrod JD. (2016) Airway epithelial homeostasis and planar cell polarity signaling depend on multiciliated cell differentiation. J Clin Investigation Insight. 1(13). pii: e88027.
  • Thamboo A, Velasquez N, Ayoub N, and Nayak JV. (2016) Distinguishing computed tomography findings in patients with empty nose syndrome. Int Forum Allergy Rhinol. doi: 10.1002/alr.21774.
  • Velasquez N, Thamboo A, Habib A-R, Huang Z, and Nayak JV. (2016) The Empty Nose Syndrome 6-item Questionnaire (ENS6Q): A validated 6-item questionnaire as a diagnostic aid for empty nose syndrome patients. Int Forum Allergy Rhinol. doi: 10.1002/alr.21842.
  • Patel ZM, Thamboo A, Rudmik L, Nayak JV, Smith TL, and Hwang PH. (2016) Surgical therapy versus continued medical therapy for medically refractory chronic rhinosinusitis: a systematic review and meta-analysis. Int Forum Allergy Rhinol. doi: 10.1002/alr.21872.
  •  “Is Empty Nose Syndrome Real? And if not, why are People Killing Themselves Over it?” February 2016. Cover story article on national newsfeed Buzzfeed.com discussing the enigmatic disease and diagnosis associated with empty nose syndrome following nasal surgery. Dr. Nayak’s research and patient advocacy featured in this article. https://www.buzzfeed.com/joeloliphint/is-empty-nose-syndrome-real-and-if-not-why-are-people-killin?utm_term=.lmaXyxAb0#.bo7pGyeOV

Caitlin O'Connell-Rodwell

I developed a collaboration with Thomas Hildebrandt at the Institute for Zoo and Wildlife Research (IZW) in Berlin to coordinate and obtain permits to receive elephant temporal bone specimens in order to collaborate with Dr. Sunil Puria and Dr. Charles Steele in 2017 on their NIH grant [NIDCD R01 grant #5R01DC005960-12: WHY DO MAMMALS HAVE A FLEXIBLE THREE-BONE OSSICULAR CHAIN?] I also met with Dr. Ricardo Chavarriaga Lozano, the Defitech Foundation Chair in Brain-machine Interface at Ecole Polytechnique Federale de Lausanne to discuss a possible collaboration and grant proposal on the vibration sense and the potential to drive the development of vibrotactle prosthetics for both hearing and limb regeneration.

In addition to my formal and informal science education outreach lectures and workshop efforts for both adults and STEM students of all ages (February at Ursinus College, PA, sponsored by HHMI), I continued my wild African elephant field studies in Etosha National Park, Namibia, sponsored through the Vice Provost Undergraduate Education (VPUE) program. In addition, I worked with the Howard Hughs Medical Institute (HHMI) to develop an online educational video on my elephant acoustic studies that will post by the end of the year.

And I became Adjunct Professor November 1.

  • Narins, P., Stoeger, A., O’Connell-Rodwell, C.E. (2016). Infrasonic and seismic communication in the vertebrates with special emphasis on the afrotheria: an update and future directions. Auditory Res., Vol. 53, Roderick A. Suthers et al. (Eds): Vertebrate Sound Production and Acoustic Communication, 191-227.

John S. Oghalai

The Oghalai laboratory is continuing to make progress on understanding the mechanisms of normal and impaired hearing. Their goal is to prevent progressive sensorineural hearing loss. Also, they hope to understand how the cochlea processes speech to improve the ability of hearing-impaired patients to understand what people are saying, even in the presence of background noise. They have developed novel technology, termed Volumetric Optical Coherence Tomography and Vibrometry (VOCTV), that uses advanced optical techniques to non-invasively measure the angstrom-level vibrations created by sound within the cochlea in living animals. They use this technology in nearly all of their on-going studies. They have identified new features of the traveling wave that tune hair cell stereociliary bundle deflection. This is important because it underlie the sharp frequency tuning of mammalian hearing. Furthermore, they have compared avian and mammalian inner ear function to learn the key functional differences between hair cells that can and cannot regenerate.

Clinically, the Stanford Children’s Hearing Center is busy managing complex pediatric hearing loss patients and is routinely accruing cochlear implant patients for clinical trials. They are performing brain-imaging in our cochlear implant recipients to maximize the ability of the implant to provide a clear understanding of speech.

Furthermore, a new educational program has been developed for the Department of Otolaryngology – Head and Neck Surgery. The Clinician-Scientist Training Program (CSTP) offers a two-year research post-doctoral fellowship training for one otolaryngology resident per year and for one post-otolaryngology resident graduate every other year. This is funded by an NIH T32 grant.

Finally, a long-awaited surgical atlas that John Oghalai has co-authored with Colin Driscoll, Chair of Otolaryngology at the Mayo Clinic, has finally been published. It is entitled Atlas of Neurotologic and Lateral Skull Base Surgery, and is intended for advanced residents in otolaryngology and neurosurgery, neurotology fellows, and junior faculty members with interests in the field.

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  • Jawadi Z, Applegate BE, Oghalai JS. (2016). Optical coherence tomography to measure sound-induced motions within the mouse organ of corti in vivo. Methods Mol Biol 1427, 449–462.
  • Kim S, Raphael PD, Oghalai JS, Applegate BE. (2016). High-speed spectral calibration by complex fir filter in phase-sensitive optical coherence tomography. Biomed Opt Express 7, 1430–1444.
  • Lee HY, Raphael PD, Xia A, Kim J, Grillet N, Applegate BE, Ellerbee Bowden AK, Oghalai JS. (2016). Two-dimensional cochlear micromechanics measured in vivo demonstrate radial tuning within the mouse organ of corti. J Neurosci 36, 8160–8173.
  • Monfared A, Corrales CE, Theodosopoulos P V, Blevins NH, Oghalai JS, Selesnick SH, Lee H, Gurgel RK, Hansen MR, Nelson RF, Gantz BJ, Kutz JW, Isaacson B, Roland PS, Amdur R, Jackler RK .(2016). Facial nerve outcome and tumor control rate as a function of degree of resection in treatment of large acoustic neuromas: preliminary report of the acoustic neuroma subtotal resection study (ansrs). Neurosurgery 79, 194–203.
  • Oghalai JS, Driscoll CLWC. (2016). Atlas of neurotologic and lateral skull base surgery. Heidelberg, Germany: Springer.
  • Oghalai JS, Jackler RK .(2016a). New web-based tool for generating scattergrams to report hearing results. Otolaryngol Head Neck Surg 154:981.
  • Olds C, Oghalai JS. (2016). Bilirubin-induced audiologic injury in preterm infants. Clin Perinatol 43, 313–323.
  • Olds C, Pollonini L, Abaya H, Larky J, Loy M, Bortfeld H, Beauchamp MS, Oghalai JS. (2016). Cortical activation patterns correlate with speech understanding after cochlear implantation. Ear Hear 37, e160–e172.
  • Saliba J, Bortfeld H, Levitin DJ, Oghalai JS. (2016). Functional near-infrared spectroscopy for neuroimaging in cochlear implant recipients. Hear Res.
  • Xia A, Liu X, Raphael PD, Applegate BE, Oghalai JS. (2016). Hair cell force generation does not amplify or tune vibrations within the chicken basilar papilla. Nat Commun 7, 13133.
  • Zeng W-Z, Grillet N, Dewey JB, Trouillet A, Krey JF, Barr-Gillespie PG, Oghalai JS, Muller U. (2016). Neuroplastin isoform np55 is expressed in the stereocilia of outer hair cells and required for normal outer hair cell function. J Neurosci 36, 9201–9216.

Tony Ricci

Over the past year we have made good progress on the three areas of research on which my lab is focused. These areas include hair cell mechanotransduction, i.e. how does sound get converted into an electrical signal, synaptic transmission, i.e. how does the sensory hair cell communicate with the brain and finally on developing novel antibiotics that do not have the debilitating side effects of ototoxicity and nephrotoxicity.

For mechanotransduction we have identified a membrane based modulation of the mechanosensitive ion channel that controls how fast the channel opens and how long it stays open. We are presently trying to understand the molecular components responsible for this sensitivity. We have also shown that the hair bundle does not move cohesively and that this property is critical to the output of the hair cells. We have several lines of work now investigation how the hair bundle moves in situ as well as in response to different forms of stimulation that may be closer to natural stimulation.

For the past year we have investigated the role of the synaptic ribbon in regulating hair cell transmission. In doing this we have developed and refined technologies for recording from postsynaptic neurons as well as for immunocytochemical characterization of these synapses. In addition, we are exploring the role of intracellular calcium on regulating synaptic vesicle trafficking.

In the last year we have obtained crystal structures of aminoglycosides with their ribosome binding partners in order to directly assess potential modification sites as well as to find correlations to antimicrobial activity. This work is helping to focus our drug design to better maintain antimicrobial activity while alleviating oto and nephron toxicity.

 

  • Peng, A. W., Gnanasambandam, R., Sachs, F. & Ricci, A. J.(2016). Adaptation independent modulation of auditory hair cell mechanotransduction channel open probability implicates a role for the lipid bilayer.J Neurosc. 36, 2945-2956.
  • Beurg, M., Goldring, A. C., Ricci, A. J. & Fettiplace, R.(2016). Development and localization of reverse-polarity mechanotransducer channels in cochlear hair cells. Proc Natl Acad Sci U S A113, 6767-6772.
  • Peng, A. W. & Ricci, A. J.(2016). Glass probe stimulation of hair cell stereocilia. Methods Mol Bio. 1427, 487-500.
  • Castellano-Munoz, M., Schnee, M. E. & Ricci, A. J. (2016). Calcium-induced calcium release supports recruitment of synaptic vesicles in auditory hair cells. J Neurophysio. 115, 226-239.

Eben Rosenthal

Our lab has recently established the feasibility of contrast enhanced cancer surgery using novel agents that permit real-time visualization of cancer.  In addition we have defined the use of antibody directed photoimmunotherapy to eliminate residual disease after gross removal of the tumor.

 

  • Moore LS, Rosenthal EL, de Boer E, Prince AC, Patel N, Richman JM, Morlandt AB, Carroll WR, Zinn KR, Warram JM. (2016). effects of an unlabeled loading dose on tumor-specific uptake of a fluorescently labeled antibody for optical surgical navigation. Mol Imaging Biol. Nov 9.
  • Moore LS, Rosenthal EL, Chung TK, de Boer E, Patel N, Prince AC, Korb ML, Walsh EM, Young ES, Stevens TM, Withrow KP, Morlandt AB, Richman J, Carroll WR, Zinn KR, Warram JM. (2016). characterizing the utilities and limitations of repurposing an open-field optical imaging device for fluorescence-guided surgery in head and neck cancer patients. J Nucl Med. 1. pii: jnumed.115.171413.
  • Moore LS, de Boer E, Warram JM, Tucker MD, Carroll WR, Korb ML, Brandwein-Gensler MS, van Dam GM, Rosenthal EL. (2016). photoimmunotherapy of residual disease after incomplete surgical resection in head and neck cancer models. Cancer Med. 5(7), 1526-34.
  • Rosenthal EL, Warram JM, de Boer E, Basilion JP, Biel MA, Bogyo M, Bouvet M, Brigman BE, Colson YL, DeMeester SR, Gurtner GC, Ishizawa T, Jacobs PM, Keereweer S, Liao JC, Nguyen QT, Olson JM, Paulsen KD, Rieves D, Sumer BD, Tweedle MF, Vahrmeijer AL, Weichert JP, Wilson BC, Zenn MR, Zinn KR, van Dam GM. (2016). successful translation of fluorescence navigation during oncologic surgery: a consensus report. J Nucl Med. 7(1), 144-50.
  • Winget M, Haji-Sheikhi F, Brown-Johnson C, Rosenthal EL, Sharp C, Buyyounouski MK, Asch SM. (2016). electronic release of pathology and radiology results to patients: opinions and experiences of oncologists. J Oncol Pract. 12(8), e792-9. 

John Sunwoo

The focus of the Sunwoo laboratory is to understand the immune response to cancer and how tumor and host factors determine the heterogeneity in this response. This past year, the group has published several papers related to this, including those in the Journal of Experimental Medicine, Clinical Cancer Research, Annals of Oncology, Oncotarget, and Biochemistry and Biophysics Reports. The work presented in two of these articles was that of two PhD graduate students in the Immunology Program. These two students, Luhua Zhang and Yunqin Lee, successfully defended their thesis work, which was performed in the Sunwoo lab under Dr. Sunwoo’s mentorship, and graduated this past summer. The Sunwoo laboratory received additional NIH funding this year through a U54 center grant that was awarded to Sylvia Plevritis, Garry Nolan, Ed Engleman, and John Sunwoo. The overall goal of this new project is to understand how metastases (of head and neck squamous cell carcinoma and of melanoma) to regional lymph nodes affect the systemic immune system and predispose patients to distant metastases. The Stanford group was one of only three centers in the nation that was funded through this mechanism this year.

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  • Shin JH, Haggadone MD, Sunwoo JB. Transcription factor Dlx3 induces aryl hydrocarbon receptor promoter activity. Biochem Biophys Rep. 2016 Sep;7:353-360.
  • Makkouk A, Sundaram V, Chester C, Chang S, Colevas AD, Sunwoo JB, Maecker H, Desai M, Kohrt HE.Characterizing CD137 Upregulation on NK cells in Patients Receiving Monoclonal Antibody Therapy. Ann Oncol. 2016 Nov 9. pii: mdw570. [Epub ahead of print]
  • Zhang LH, Shin JH, Haggadone MD, Sunwoo JB. The aryl hydrocarbon receptor is required for the maintenance of liver-resident natural killer cells. J Exp Med. 2016 Oct 17;213(11):2249-2257.
  • Flexible radioluminescence imaging for FDG-guided surgery. King MT, Jenkins CH, Sun C, Carpenter CM, Ma X, Cheng K, Le QT, Sunwoo JB, Cheng Z, Pratx G, Xing L. Med Phys. 2016 Oct;43(10):5298.
  • Chen C, Shin JH, Eggold JT, Chung MK, Zhang LH, Lee J, Sunwoo JB. ESM1 mediates NGFR-induced invasion and metastasis in murine oral squamous cell carcinoma. Oncotarget. 2016 Sep 23. doi: 10.18632/oncotarget.12210. [Epub ahead of print]
  • Brennan K, Holsinger C, Dosiou C, Sunwoo JB, Akatsu H, Haile R, Gevaert O. Development of prognostic signatures for intermediate-risk papillary thyroid cancer. BMC Cancer. 2016 Sep 15;16(1):736
  • Brooks JD, Wei W, Pollack JR, West RB, Shin JH, Sunwoo JB, Hawley SJ, Auman H, Newcomb LF, Simko J, Hurtado-Coll A, Troyer DA, Carroll PR, Gleave ME, Lin DW, Nelson PS, Thompson IM, True LD, McKenney JK, Feng Z, Fazli L. Loss of Expression of AZGP1 Is Associated With Worse Clinical Outcomes in a Multi-Institutional Radical Prostatectomy Cohort. Prostate. 2016 Nov;76(15):1409-19. doi: 10.1002/pros.23225.
  • Uppaluri R, Bell RB, Sunwoo JB. Head and neck cancer immunology and immunotherapeutics: Basic concepts to clinical translational approaches. Oral Oncol. 2016 Jul;58:49-51.
  • Lee Y, Shin JH, Longmire M, Wang H, Kohrt HE, Chang HY, Sunwoo JB. CD44+ Cells in Head and Neck Squamous Cell Carcinoma Suppress T-Cell-Mediated Immunity by Selective Constitutive and Inducible Expression of PD-L1. Clin Cancer Res. 2016 Jul 15;22(14):3571-81. 

Contributions by the individual laboratory heads. Summary by Research Vice Chair Stefan Heller, PhD.