{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T03:32:55Z","timestamp":1777606375423,"version":"3.51.4"},"reference-count":92,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,1]],"date-time":"2023-04-01T00:00:00Z","timestamp":1680307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIDCD","award":["R01 DC015824"],"award-info":[{"award-number":["R01 DC015824"]}]},{"name":"Larry Bowman","award":["R01 DC015824"],"award-info":[{"award-number":["R01 DC015824"]}]},{"name":"Remondi Foundation","award":["R01 DC015824"],"award-info":[{"award-number":["R01 DC015824"]}]},{"name":"Bertarelli Foundation Endowed Professorship","award":["R01 DC015824"],"award-info":[{"award-number":["R01 DC015824"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Vestibular schwannoma (VS) is an intracranial tumor that commonly presents with tinnitus and hearing loss. To uncover the molecular mechanisms underlying VS-associated tinnitus, we applied next-generation sequencing (Illumina HiSeq) to formalin-fixed paraffin-embedded archival VS samples from nine patients with tinnitus (VS-Tin) and seven patients without tinnitus (VS-NoTin). Bioinformatic analysis was used to detect differentially expressed genes (DEG; i.e., \u2265two-fold change [FC]) while correcting for multiple comparisons. Using RNA-seq analysis, VS-Tin had significantly lower expression of GFAP (logFC = \u22123.04), APLNR (logFC = \u22122.95), PREX2 (logFC = \u22121.44), and PLVAP (logFC = \u22121.04; all p &lt; 0.01) vs. VS-NoTin. These trends were validated by using real-time RT-qPCR. At the protein level, immunohistochemistry revealed a trend for less PREX2 and apelin expression and greater expression of NLRP3 inflammasome and CD68-positive macrophages in VS-Tin than in VS-NoTin, suggesting the activation of inflammatory processes in VS-Tin. Functional enrichment analysis revealed that the top three protein categories\u2014glycoproteins, signal peptides, and secreted proteins\u2014were significantly enriched in VS-Tin in comparison with VS-NoTin. In a gene set enrichment analysis, the top pathway was allograft rejection, an inflammatory pathway that includes the MMP9, CXCL9, IL16, PF4, ITK, and ACVR2A genes. Future studies are needed to examine the importance of these candidates and of inflammation in VS-associated tinnitus.<\/jats:p>","DOI":"10.3390\/jcm12072642","type":"journal-article","created":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T02:10:13Z","timestamp":1680487813000},"page":"2642","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Comparative Transcriptomic Analysis of Archival Human Vestibular Schwannoma Tissue from Patients with and without Tinnitus"],"prefix":"10.3390","volume":"12","author":[{"given":"Krishna","family":"Bommakanti","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA 02114, USA"},{"name":"Department of Head and Neck Surgery, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Seist","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA 02114, USA"},{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA"},{"name":"Department of Otorhinolaryngology\u2013Head and Neck Surgery, Paracelsus Medical University, 5020 Salzburg, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4790-386X","authenticated-orcid":false,"given":"Phanidhar","family":"Kukutla","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murat","family":"Cetinbas","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shelley","family":"Batts","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruslan I.","family":"Sadreyev","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anat","family":"Stemmer-Rachamimov","sequence":"additional","affiliation":[{"name":"Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4586-1723","authenticated-orcid":false,"given":"Gary J.","family":"Brenner","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantina M.","family":"Stankovic","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA 02114, USA"},{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA"},{"name":"Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA"},{"name":"Wu Tsai Neuroscience Institute, Stanford University, Stanford, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,1]]},"reference":[{"key":"ref_1","first-page":"347","article-title":"Analysis of patterns of care of brain tumor patients in the United States: A study of the Brain Tumor Section of the AANS and the CNS and the Commission on Cancer of the ACS","volume":"36","author":"Mahaley","year":"1990","journal-title":"Clin. Neurosurg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1056\/NEJMra2020394","article-title":"Vestibular schwannomas","volume":"384","author":"Carlson","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"466","DOI":"10.7162\/S1809-97772012000400007","article-title":"Vestibular schwannoma: 825 cases from a 25-year experience","volume":"16","author":"Pinna","year":"2012","journal-title":"Int. Arch. Otorhinolaryngol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1136\/jnnp.66.6.764","article-title":"Probability of bilateral disease in people presenting with a unilateral vestibular schwannoma","volume":"66","author":"Evans","year":"1999","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/00006123-199704000-00006","article-title":"Management of 1000 vestibular schwannomas (acoustic neuromas): Clinical presentation","volume":"40","author":"Samii","year":"1997","journal-title":"Neurosurgery"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1044\/1092-4388(2005\/084)","article-title":"General review of tinnitus: Prevalence, mechanisms, effects, and management","volume":"48","author":"Henry","year":"2005","journal-title":"J. Speech Lang. Hear. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1097\/MAO.0000000000001190","article-title":"Hearing loss progresses faster in patients with growing intracanalicular vestibular schwannomas","volume":"37","author":"Borsboom","year":"2016","journal-title":"Otol. Neurotol."},{"key":"ref_8","unstructured":"Sheikh, M.M., and Jesus, O.D. (2023, January 31). Vestibular schwannoma. [Updated 26 November 2022], StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK562312\/."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.4103\/sni.sni_129_16","article-title":"Clinical features, microsurgical treatment, and outcome of vestibular schwannoma with brainstem compression","volume":"8","author":"Harati","year":"2017","journal-title":"Surg. Neurol. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1001\/archotol.133.1.56","article-title":"Assessing impairment and disability of facial paralysis in patients with vestibular schwannoma","volume":"133","author":"Lee","year":"2007","journal-title":"Arch. Otolaryngol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.3174\/ajnr.A5213","article-title":"The management and imaging of vestibular schwannomas","volume":"38","author":"Lin","year":"2017","journal-title":"Am. J. Neuroradiol."},{"key":"ref_12","unstructured":"Mayo Clinic (2023, February 27). Acoustic Neuroma. Available online: https:\/\/www.mayoclinic.org\/diseases-conditions\/acoustic-neuroma\/care-at-mayo-clinic\/mac-20356135."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1007\/s00405-012-2248-4","article-title":"Management of growing vestibular schwannomas","volume":"270","author":"Ferri","year":"2013","journal-title":"Eur. Arch. Oto-Rhino-Laryngol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1097\/MOO.0b013e328357d337","article-title":"Radiation therapy for vestibular schwannomas","volume":"20","author":"Mulder","year":"2012","journal-title":"Curr. Opin. Otolaryngol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1001\/jamaoto.2016.1700","article-title":"Prevalence, severity, exposures, and treatment patterns of tinnitus in the United States","volume":"142","author":"Bhatt","year":"2016","journal-title":"JAMA Otolaryngol. Head Neck Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"152","DOI":"10.3171\/2009.3.JNS081053","article-title":"Effect of tumor removal on tinnitus in patients with vestibular schwannoma: Clinical article","volume":"112","author":"Kameda","year":"2010","journal-title":"J. Neurosurg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1038\/s41598-019-38582-y","article-title":"Changes in tinnitus after vestibular schwannoma surgery","volume":"9","author":"Wang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1055\/s-2005-926216","article-title":"The clinical characteristics of tinnitus in patients with vestibular schwannoma","volume":"16","author":"Baguley","year":"2006","journal-title":"Skull Base"},{"key":"ref_19","first-page":"82","article-title":"Clinical acumen and vestibular schwannoma","volume":"19","author":"Moffat","year":"1998","journal-title":"Am. J. Otol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1002\/lary.25110","article-title":"What drives quality of life in patients with sporadic vestibular schwannoma?","volume":"125","author":"Carlson","year":"2015","journal-title":"Laryngoscope"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1016\/j.mayocp.2020.03.033","article-title":"Beyond the ABCs: Hearing loss and quality of life in vestibular schwannoma","volume":"95","author":"Graffeo","year":"2020","journal-title":"Mayo Clin. Proc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"378","DOI":"10.3389\/fneur.2017.00378","article-title":"Predictors of preoperative tinnitus in unilateral sporadic vestibular schwannoma","volume":"8","author":"Naros","year":"2017","journal-title":"Front. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1007\/s10162-021-00815-1","article-title":"Too blind to see the elephant? Why neuroscientists ought to be interested in tinnitus","volume":"22","author":"Knipper","year":"2021","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"597","DOI":"10.3389\/fnins.2016.00597","article-title":"Stochastic resonance controlled upregulation of internal noise after hearing loss as a putative cause of tinnitus-related neuronal hyperactivity","volume":"10","author":"Krauss","year":"2016","journal-title":"Front. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.tins.2004.08.010","article-title":"The neuroscience of tinnitus","volume":"27","author":"Eggermont","year":"2004","journal-title":"Trends Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/0168-0102(90)90031-9","article-title":"Phantom auditory perception (tinnitus): Mechanisms of generation and perception","volume":"8","author":"Jastreboff","year":"1990","journal-title":"Neurosci. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"836504","DOI":"10.3389\/fonc.2022.836504","article-title":"Sporadic vestibular schwannoma size and location do not correlate with the severity of hearing loss at initial presentation","volume":"12","author":"Brown","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1177\/0194599816642427","article-title":"The persistence of tinnitus after acoustic neuroma surgery","volume":"155","author":"Bell","year":"2016","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"vdaa023","DOI":"10.1093\/noajnl\/vdaa023","article-title":"The inflammatory microenvironment in vestibular schwannoma","volume":"2","author":"Hannan","year":"2020","journal-title":"Neuro-Oncol. Adv."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Mennink, L.M., Aalbers, M.W., van Dijk, P., and van Dijk, J.M.C. (2022). The role of inflammation in tinnitus: A systematic review and meta-analysis. J. Clin. Med., 11.","DOI":"10.3390\/jcm11041000"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"796","DOI":"10.3389\/fneur.2020.00796","article-title":"Progression of contralateral hearing loss in patients with sporadic vestibular schwannoma","volume":"11","author":"Early","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1002\/acn3.51386","article-title":"Transcriptomic signature of painful human neurofibromatosis type 2 schwannomas","volume":"8","author":"Kukutla","year":"2021","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3988\/jcn.2009.5.1.11","article-title":"Tinnitus: Characteristics, causes, mechanisms, and treatments","volume":"5","author":"Han","year":"2009","journal-title":"J. Clin. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/978-981-13-6123-4_7","article-title":"Advances in understanding, diagnosis, and treatment of tinnitus","volume":"1130","author":"Tang","year":"2019","journal-title":"Adv. Exp. Med. Biol"},{"key":"ref_35","first-page":"S1","article-title":"Clinical practice guideline: Tinnitus","volume":"151","author":"Tunkel","year":"2014","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5049","DOI":"10.1158\/1078-0432.CCR-20-3251","article-title":"Cross-site concordance evaluation of tumor DNA and RNA sequencing platforms for the CIMAC-CIDC Network","volume":"27","author":"Zeng","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1093\/bioinformatics\/btac166","article-title":"Analysing high-throughput sequencing data in Python with HTSeq 2.0","volume":"38","author":"Putri","year":"2022","journal-title":"Bioinformatics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic. Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"107770","DOI":"10.1016\/j.heares.2019.07.007","article-title":"NLRP3 inflammasome activation in human vestibular schwannoma: Implications for tumor-induced hearing loss","volume":"381","author":"Sagers","year":"2019","journal-title":"Hear. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0378-5955(03)00298-3","article-title":"Real-time quantitative RT-PCR for low-abundance transcripts in the inner ear: Analysis of neurotrophic factor expression","volume":"185","author":"Stankovic","year":"2003","journal-title":"Hear. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11268","DOI":"10.1038\/ncomms11268","article-title":"MicroRNA 139-5p coordinates APLNR-CXCR4 crosstalk during vascular maturation","volume":"7","author":"Papangeli","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_46","first-page":"769","article-title":"Can apelin play a role in the etiology of tinnitus?","volume":"49","author":"Ensari","year":"2019","journal-title":"Turk. J. Med. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s10162-021-00786-3","article-title":"Transient delivery of a KCNQ2\/3-specific channel activator 1 week after noise trauma mitigates noise-induced tinnitus","volume":"22","author":"Marinos","year":"2021","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1097\/00007890-200205150-00001","article-title":"Multiple pathways to allograft rejection","volume":"73","author":"Goldman","year":"2002","journal-title":"Transplantation"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/7854_2021_238","article-title":"Neuroinflammation and tinnitus","volume":"51","author":"Shulman","year":"2021","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.heares.2014.10.007","article-title":"Biological correlates of tinnitus-related distress: An exploratory study","volume":"318","author":"Szczepek","year":"2014","journal-title":"Hear. Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Wang, W., Zhang, L.S., Zinsmaier, A.K., Patterson, G., Leptich, E.J., Shoemaker, S.L., Yatskievych, T.A., Gibboni, R., Pace, E., and Luo, H. (2019). Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models. PLoS Biol., 17.","DOI":"10.1371\/journal.pbio.3000307"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1016\/S0006-291X(02)02077-6","article-title":"Inhibition of NF-\u03baB activation by merlin","volume":"296","author":"Kim","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.trre.2011.07.005","article-title":"Role of T cell-nuclear factor \u03baB in transplantation","volume":"26","author":"Molinero","year":"2012","journal-title":"Transplant. Rev."},{"key":"ref_54","first-page":"6231","article-title":"Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: Evidence for a positive autoregulatory loop","volume":"13","author":"Hiscott","year":"1993","journal-title":"Mol. Cell. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s40136-018-0186-4","article-title":"The role of tumor necrosis factor alpha (TNF\u03b1) in hearing loss and vestibular schwannomas","volume":"6","author":"Ren","year":"2018","journal-title":"Curr. Otorhinolaryngol. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"18599","DOI":"10.1038\/srep18599","article-title":"Secreted factors from human vestibular schwannomas can cause cochlear damage","volume":"5","author":"Dilwali","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1016\/j.molonc.2015.03.009","article-title":"Preclinical validation of anti-nuclear factor-kappa B therapy to inhibit human vestibular schwannoma growth","volume":"9","author":"Dilwali","year":"2015","journal-title":"Mol. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.3389\/fneur.2019.01353","article-title":"Intracochlear perfusion of tumor necrosis factor-alpha induces sensorineural hearing loss and synaptic degeneration in guinea pigs","volume":"10","author":"Katsumi","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1161\/STROKEAHA.110.593327","article-title":"Tumor necrosis factor-\u03b1 enhances microvascular tone and reduces blood flow in the cochlea via enhanced sphingosine-1-phosphate signaling","volume":"41","author":"Scherer","year":"2010","journal-title":"Stroke"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.ccell.2019.05.004","article-title":"Cooperation between constitutive and inducible chemokines enables t cell engraftment and immune attack in solid tumors","volume":"35","author":"Dangaj","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41417-021-00303-x","article-title":"Key chemokines direct migration of immune cells in solid tumors","volume":"29","author":"Kohli","year":"2022","journal-title":"Cancer Gene Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ctrv.2017.11.007","article-title":"CXCL9, CXCL10, CXCL11\/CXCR3 axis for immune activation\u2014A target for novel cancer therapy","volume":"63","author":"Tokunaga","year":"2018","journal-title":"Cancer Treat. Rev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1074\/jbc.M204544200","article-title":"The transcriptional coactivator CREB-binding protein cooperates with STAT1 and NF-\u03baB for synergistic transcriptional activation of the CXC Ligand 9\/monokine induced by Interferon-\u03b3 gene","volume":"278","author":"Hiroi","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1038\/s41416-022-01763-0","article-title":"CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer","volume":"126","author":"Seitz","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3246","DOI":"10.1002\/cam4.934","article-title":"CXCL9: Evidence and contradictions for its role in tumor progression","volume":"5","author":"Ding","year":"2016","journal-title":"Cancer Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"ra32","DOI":"10.1126\/scisignal.2005840","article-title":"PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion","volume":"8","author":"Mense","year":"2015","journal-title":"Sci. Signal."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4564","DOI":"10.1158\/1078-0432.CCR-12-1662","article-title":"Molecular pathways: P-Rex in cancer","volume":"19","author":"Pandiella","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1126\/science.1173569","article-title":"Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a","volume":"325","author":"Fine","year":"2009","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1038\/s41598-018-36810-5","article-title":"Somatic mutations of PREX2 gene in patients with hepatocellular carcinoma","volume":"9","author":"Yang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e21504","DOI":"10.1200\/JCO.2021.39.15_suppl.e21504","article-title":"PREX2 mutation serves as a novel predictor of response to anti-PD-1\/PD-L1 treatment in melanoma","volume":"39","author":"Cai","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/nature11071","article-title":"Melanoma genome sequencing reveals frequent PREX2 mutations","volume":"485","author":"Berger","year":"2012","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1080\/01616412.2017.1376494","article-title":"Reduced RAC1 activity inhibits cell proliferation and induces apoptosis in neurofibromatosis type 2(NF2)-associated schwannoma","volume":"39","author":"Wang","year":"2017","journal-title":"Neurol. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"731441","DOI":"10.3389\/fonc.2021.731441","article-title":"Potential molecular biomarkers of vestibular schwannoma growth: Progress and prospects","volume":"11","author":"Zhang","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1097\/MAO.0b013e3181f20655","article-title":"MicroRNA-21 overexpression contributes to vestibular schwannoma cell proliferation and survival","volume":"31","author":"Cioffi","year":"2010","journal-title":"Otol. Neurotol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1046\/j.1365-2559.2002.01398.x","article-title":"PTEN is not altered in sporadic vestibular schwannomas","volume":"40","author":"Mawrin","year":"2002","journal-title":"Histopathology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"101956","DOI":"10.1016\/j.jchemneu.2021.101956","article-title":"Apelin-13 prevents apoptosis in the cochlear tissue of noise-exposed rat via Sirt-1 regulation","volume":"114","author":"Khoshsirat","year":"2021","journal-title":"J. Chem. Neuroanat."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"134948","DOI":"10.1016\/j.neulet.2020.134948","article-title":"Apelin protects auditory cells from cisplatin-induced toxicity in vitro by inhibiting ROS and apoptosis","volume":"728","author":"Yin","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"848","DOI":"10.3892\/ijo.2013.1798","article-title":"Microarray analysis of gene expression in vestibular schwannomas reveals SPP1\/MET signaling pathway and androgen receptor deregulation","volume":"42","author":"Lassaletta","year":"2013","journal-title":"Int. J. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1097\/MAO.0000000000002116","article-title":"Objective measures of tinnitus: A systematic review","volume":"40","author":"Jackson","year":"2019","journal-title":"Otol. Neurotol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"382","DOI":"10.5152\/iao.2022.21541","article-title":"Cochlear implantation for patients with a vestibular schwannoma: Effect on tinnitus handicap","volume":"18","author":"West","year":"2022","journal-title":"J. Int. Adv. Otol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"646014","DOI":"10.3389\/fneur.2021.646014","article-title":"Repetitive transcranial magnetic stimulation for tinnitus treatment in vestibular schwannoma: A pilot study","volume":"12","author":"Leao","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_82","first-page":"8","article-title":"Subjective benefits reported by adult Nucleus 22-channel cochlear implant users","volume":"23","author":"Kou","year":"1994","journal-title":"J. Otolaryngol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"527","DOI":"10.3109\/14992020209056073","article-title":"Tinnitus in cochlear implant patients--a comparison with other hearing-impaired patients","volume":"41","author":"Mo","year":"2002","journal-title":"Int. J. Audiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e425","DOI":"10.1097\/MAO.0000000000002978","article-title":"Cochlear Implantation in Sporadic Vestibular Schwannoma and Other Retrocochlear Pathology: A Case Series","volume":"42","author":"Patel","year":"2021","journal-title":"Otol. Neurotol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"E9","DOI":"10.3171\/2017.12.FOCUS17670","article-title":"Simultaneous cochlear implantation as a therapeutic option in vestibular schwannoma surgery: Case report","volume":"44","author":"Zamponi","year":"2018","journal-title":"Neurosurg. Focus"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1097\/MAO.0000000000001570","article-title":"Prospective evaluation of patients undergoing translabyrinthine excision of vestibular schwannoma with concurrent cochlear implantation","volume":"38","author":"Rooth","year":"2017","journal-title":"Otol. Neurotol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1007\/s00405-015-3801-8","article-title":"Cochlear implantation for hearing rehabilitation in single-sided deafness after translabyrinthine vestibular schwannoma surgery","volume":"273","author":"Hassepass","year":"2016","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"257","DOI":"10.3766\/jaaa.18.3.7","article-title":"The impact of tinnitus on quality of life in older adults","volume":"18","author":"Nondahl","year":"2007","journal-title":"J. Am. Acad. Audiol."},{"key":"ref_89","first-page":"125","article-title":"Psychological stress and impaired quality of life in patients with tinnitus","volume":"52","author":"Maurischat","year":"2004","journal-title":"HNO"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1185\/03007995.2011.595781","article-title":"A review of tinnitus symptoms beyond \u2018ringing in the ears\u2019: A call to action","volume":"27","author":"Langguth","year":"2011","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1477-7525-12-7","article-title":"Which tinnitus-related aspects are relevant for quality of life and depression: Results from a large international multicentre sample","volume":"12","author":"Zeman","year":"2014","journal-title":"Health Qual. Life Outcomes"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/j.mcna.2018.06.014","article-title":"Tinnitus","volume":"102","author":"Chari","year":"2018","journal-title":"Med. Clin. N. 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