Browsing by Author "Yates, Charles W."
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Item Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK(PLOS, 2021-07-15) Chang, Long-Sheng; Oblinger, Janet L.; Smith, Abbi E.; Ferrer, Marc; Angus, Steven P.; Hawley, Eric; Petrilli, Alejandra M.; Beauchamp, Roberta L.; Riecken, Lars Björn; Erdin, Serkan; Poi, Ming; Huang, Jie; Bessler, Waylan K.; Zhang, Xiaohu; Guha, Rajarshi; Thomas, Craig; Burns, Sarah S.; Gilbert, Thomas S.K.; Jiang, Li; Li, Xiaohong; Lu, Qingbo; Yuan, Jin; He, Yongzheng; Dixon, Shelley A.H.; Masters, Andrea; Jones, David R.; Yates, Charles W.; Haggarty, Stephen J.; La Rosa, Salvatore; Welling, D. Bradley; Stemmer-Rachamimov, Anat O.; Plotkin, Scott R.; Gusella, James F.; Guinney, Justin; Morrison, Helen; Ramesh, Vijaya; Fernandez-Valle, Cristina; Johnson, Gary L.; Blakeley, Jaishri O.; Clapp, D. Wade; Pediatrics, School of MedicineNeurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies.Item Chemopreventative celecoxib fails to prevent schwannoma formation or sensorineural hearing loss in genetically engineered murine model of neurofibromatosis type 2(Impact Journals, 2017-10-24) Wahle, Benjamin M.; Hawley, Eric T.; He, Yongzheng; Smith, Abbi E.; Yuan, Jin; Masters, Andi R.; Jones, David R.; Gehlhausen, Jeffrey R.; Park, Su-Jung; Conway, Simon J.; Clapp, D. Wade; Yates, Charles W.; Otolaryngology -- Head and Neck Surgery, School of MedicineMutations in the tumor suppressor gene NF2 lead to Neurofibromatosis type 2 (NF2), a tumor predisposition syndrome characterized by the development of schwannomas, including bilateral vestibular schwannomas with complete penetrance. Recent work has implicated the importance of COX-2 in schwannoma growth. Using a genetically engineered murine model of NF2, we demonstrate that selective inhibition of COX-2 with celecoxib fails to prevent the spontaneous development of schwannomas or sensorineural hearing loss in vivo, despite elevated expression levels of COX-2 in Nf2-deficient tumor tissue. These results suggest that COX-2 is nonessential to schwannomagenesis and that the proposed tumor suppressive effects of NSAIDs on schwannomas may occur through COX-2 independent mechanisms.Item Defining Inner Ear Cell Type Specification at Single-Cell Resolution in a Model of Human Cranial Development(2022-07) Steinhart, Matthew Reed; Meyer, Jason S.; Koehler, Karl R.; Herbert, Brittney-Shea; Landreth, Gary E.; Shearer, A. Eliot; Yates, Charles W.Inner ear development requires the complex interaction of numerous cell types arising from multiple embryologic origins. Current knowledge of inner ear organogenesis is limited primarily to animal models. Although most mechanisms of cellular development show conservation between vertebrate species, there are uniquely human aspects of inner ear development which remain unknown. Our group recently described a model of in vitro human inner ear organogenesis using pluripotent stem cells in a 3D organoid culture system. This method promotes the formation of an entire sensorineural circuit, including hair cells, inner ear neurons, and Schwann cells. Our past work has characterized certain aspects of this culture system, however we have yet to fully define all the cell types which contribute to inner ear organoid assembly. Here, our goal was to reconstruct a time-based map of in vitro development during inner ear organoid induction to understand the developmental elements captured in this system. We analyzed inner ear organoid development using single-cell RNA sequencing at ten time points during the first 36 days of induction. We reconstructed the on-target progression of undifferentiated pluripotent stem cells to surface ectoderm, pre-placodal, and otic epithelial cells, including supporting cells, hair cells, and neurons, following treatment with FGF, BMP, and WNT signaling modulators. Our data revealed endogenous signaling pathwayrelated gene expression that may influence the course of on-target differentiation. In addition, we classified a diverse array of off-target ectodermal cell types encompassing the neuroectoderm, neural crest, and mesenchymal lineages. Our work establishes the Inner ear Organoid Developmental Atlas (IODA), which can provide insights needed for understanding human biology and refining the guided differentiation of in vitro inner ear tissue.Item Extraordinary Speech and Language Outcomes After Auditory Brainstem Implantation: Guidance From a Case Study(American Speech-Language-Hearing Association, 2023) Herbert, Carolyn J.; Kronenberger, William G.; Wolfert, Kim; Nelson, Rick F.; Yates, Charles W.; Pisoni, David B.; Otolaryngology -- Head and Neck Surgery, School of MedicinePurpose: Large individual differences and poor speech recognition outcomes are routinely observed in most patients who have received auditory brainstem implants (ABIs). A case report of an ABI recipient with exceptionally good speech recognition outcomes presents an opportunity to better understand the core information processing mechanisms that underlie variability and individual differences in outcomes. Method: A case study is reported of an adult ABI recipient (ID-006) with postlingually acquired, Neurofibromatosis Type 2 (NF2)-related hearing loss who displayed exceptional postoperative speech recognition scores. A novel battery of assessment measures was used to evaluate ID-006's auditory, cognitive, and linguistic information processing skills. Results: Seventeen years following ABI activation, ID-006 scored 77.6% correct on the AzBio Sentences in quiet. On auditory processing tasks, ID-006 scored higher on tasks with meaningful sentences and much lower on tasks that relied exclusively on audibility. ID-006 also demonstrated exceptionally strong abilities on several cognitive and linguistic information processing tasks. Conclusions: Results from a novel battery of information processing tests suggest that ID-006 relies extensively on top-down predictive processing and cognitive control strategies to efficiently encode and process auditory information provided by his ABI. Results suggest that current measures of outcomes and benefits should be expanded beyond conventional speech recognition measures to include more sensitive and robust measures of speech recognition as well as neurocognitive measures such as executive function, working memory, and lexical access.Item Outpatient management of cholesteatoma with canal wall reconstruction tympanomastoidectomy(Wiley, 2017-10-31) Kao, Richard; Wannemuehler, Todd; Yates, Charles W.; Nelson, Rick F.; Otolaryngology -- Head and Neck Surgery, School of MedicineObjectives The postoperative wound infection rate for canal wall reconstruction (CWR) tympanomastoidectomy with mastoid obliteration in the treatment of chronic otitis media with cholesteatoma has been reported to be 3.6%. Postoperative administration of 24–48 hours of intravenous antibiotics has been recommended. We aim to determine the infection rate of CWR with postoperative outpatient oral antibiotics. Study Design Institutional review board—approved retrospective case review. Setting Tertiary referral center. Patients: Retrospective review of consecutive patients who underwent CWR tympanomastoidectomy with mastoid obliteration at a single institution from 2014 to 2016. Main Outcome Measure: Patient characteristics (age, sex) were calculated. Rate of postoperative complications and infections within 1 month of surgery were calculated. Comparison to previous published infection rates with postoperative intravenous antibiotics. Results 51 patients underwent CWR followed by outpatient oral antibiotics with a mean age of 25.9 years (16 patients were less than 10 years old). There were no postoperative wound infections. Outpatient antibiotics showed non-inferiority to IV antibiotic historic controls (0% vs. 3.6%; 95% confidence interval [CI], 0–6.09%; p = 0.03). One patient had small postoperative wound dehiscence with CSF leak that was managed conservatively. One patient developed Clostridium difficile colitis on postoperative day 2. Conclusions The infection rate after CWR tympanomastoidectomy with use of outpatient antibiotics is low and is non-inferior to a historic cohort treated with inpatient intravenous antibiotics. A larger randomized controlled trial is warranted. Level of Evidence 4.Item A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas(Oxford University Press, 2019-02-15) Gehlhausen, Jeffrey R.; Hawley, Eric; Wahle, Benjamin Mark; He, Yongzheng; Edwards, Donna; Rhodes, Steven D.; Lajiness, Jacquelyn D.; Staser, Karl; Chen, Shi; Yang, Xianlin; Yuan, Jin; Li, Xiaohong; Jiang, Li; Smith, Abbi; Bessler, Waylan; Sandusky, George; Stemmer-Rachamimov, Anat; Stuhlmiller, Timothy J.; Angus, Steven P.; Johnson, Gary L.; Nalepa, Grzegorz; Yates, Charles W.; Clapp, D. Wade; Park, Su-Jung; Pediatrics, School of MedicineSchwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.Item Reduction of sporadic and neurofibromatosis type 2-associated vestibular schwannoma growth in vitro and in vivo after treatment with the c-Jun N-terminal kinase inhibitor AS602801(American Association of Neurological Surgeons, 2022-09-09) Dougherty, Mark C.; Shibata, Seiji B.; Clark, J. Jason; Canady, Franklin J.; Yates, Charles W.; Hansen, Marlan R.; Otolaryngology -- Head and Neck Surgery, School of MedicineObjective: Vestibular schwannomas (VSs) are benign nerve sheath tumors that result from mutation in the tumor suppressor gene NF2, with functional loss of the protein merlin. The authors have previously shown that c-Jun N-terminal kinase (JNK) is constitutively active in human VS cells and plays a central role in their survival by suppressing accumulation of mitochondrial superoxides, implicating JNK inhibitors as a potential systemic treatment for VS. Thus, the authors hypothesized that the adenosine 5'-triphosphate-competitive JNK inhibitor AS602801 would demonstrate antitumor activity in multiple VS models. Methods: Treatment with AS602801 was tested in primary human VS cultures, human VS xenografts, and a genetic mouse model of schwannoma (Postn-Cre;Nf2flox/flox). Primary human VS cell cultures were established from freshly obtained surgical tumor specimens; treatment group media was enriched with AS602801. VS xenograft tumors were established in male athymic nude mice from freshly collected human tumor. Four weeks postimplantation, a pretreatment MRI scan was obtained, followed by 65 days of AS602801 (n = 18) or vehicle control (n = 19) treatment. Posttreatment MRI scans were used to measure final tumor volume. Tumors were then harvested. Finally, Postn-Cre;Nf2flox/flox mice were treated with AS602801 (n = 10) or a vehicle (n = 13) for 65 days. Posttreatment auditory brainstem responses were obtained. Dorsal root ganglia from Postn-Cre;Nf2flox/flox mice were then harvested. In all models, schwannoma identity was confirmed with anti-S100 staining, cell proliferation was measured with the EdU assay, and cell death was measured with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. All protocols were approved by the local institutional review board and Institutional Animal Care and Use Committees. Results: Treatment with AS602801 decreased cell proliferation and increased apoptosis in primary human VS cultures. The systemic administration of AS602801 in mice with human VS xenografts reduced tumor volume and cell proliferation. Last, the AS602801-treated Postn-Cre;Nf2flox/flox mice demonstrated decreased cell proliferation in glial cells in the dorsal root ganglia. However, AS602801 did not significantly delay hearing loss in Postn-Cre;Nf2flox/flox mice up to 3 months posttreatment. Conclusions: The data suggest that JNK inhibition with AS602801 suppresses growth of sporadic and neurofibromatosis type 2-associated VSs. As such, AS602801 is a potential systemic therapy for VS and warrants further investigation.Item Speech Recognition Outcomes in Adults With Slim Straight and Slim Modiolar Cochlear Implant Electrode Arrays(Springer, 2022-05) MacPhail, Margaret E.; Connell, Nathan T.; Totten, Douglas J.; Gray, Mitchell T.; Pisoni, David; Yates, Charles W.; Nelson, Rick F.; Otolaryngology -- Head and Neck Surgery, School of MedicineObjective To compare differences in audiologic outcomes between slim modiolar electrode (SME) CI532 and slim lateral wall electrode (SLW) CI522 cochlear implant recipients. Study Design Retrospective cohort study. Setting Tertiary academic hospital. Methods Comparison of postoperative AzBio sentence scores in quiet (percentage correct) in adult cochlear implant recipients with SME or SLW matched for preoperative AzBio sentence scores in quiet and aided and unaided pure tone average. Results Patients with SLW (n = 52) and patients with SME (n = 37) had a similar mean (SD) age (62.0 [18.2] vs 62.6 [14.6] years, respectively), mean preoperative aided pure tone average (55.9 [20.4] vs 58.1 [16.4] dB; P = .59), and mean AzBio score (percentage correct, 11.1% [13.3%] vs 8.0% [11.5%]; P = .25). At last follow-up (SLW vs SME, 9.0 [2.9] vs 9.9 [2.6] months), postoperative mean AzBio scores in quiet were not significantly different (percentage correct, 70.8% [21.3%] vs 65.6% [24.5%]; P = .29), and data log usage was similar (12.9 [4.0] vs 11.3 [4.1] hours; P = .07). In patients with preoperative AzBio <10% correct, the 6-month mean AzBio scores were significantly better with SLW than SME (percentage correct, 70.6% [22.9%] vs 53.9% [30.3%]; P = .02). The intraoperative tip rollover rate was 8% for SME and 0% for SLW. Conclusions Cochlear implantation with SLW and SME provides comparable improvement in audiologic functioning. SME does not exhibit superior speech recognition outcomes when compared with SLW.