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1.
Phytother Res ; 2024 Jul 17.
Article in English | MEDLINE | ID: mdl-39020450

ABSTRACT

At the end of the 2019 coronavirus pandemic (COVID-19), highly contagious variants of coronaviruses had emerged. Together with influenza viruses, different variants of the coronavirus currently cause most colds and require appropriate drug treatment. We have investigated the expression of important factors for the replication of these viruses, namely transmembrane protease serine subtype 2 (TMPRSS2), neuropilin1 (NRP1), and angiotensin converting enzyme 2 (ACE2) or tumor necrosis factor-α (TNF-α) after toll like receptor-3 (TLR-3) stimulation using RT-qPCR and flow cytometry (FC) analysis. As model served primary fibroblasts derived from the lung and nasal cavity, as well as epidermal stem cells and fully matured respiratory epithelium. The stimulated cell cultures were treated with pharmaceuticals (Dexamethasone and Enzalutamide) and the outcome was compared with the phytomedicine 1,8-Cineol. The stimulation of TLR3 is sufficient to induce the expression of exactly those targets that were highly expressed in the corresponding culture type, specifically ACE2 and TMPRSS2 in respiratory epithelial stem cells and NRP1 in fibroblast cells. It seems this self-perpetuating cycle of infection-driven upregulation of key viral replication factors by the innate immune system represents an evolutionary advantage for viruses using these transcripts as viral replication factors. Likewise, to the standard pharmaceuticals with proven clinical efficiency, 1,8-Cineol was able to disrupt this self-perpetuating cycle. Considering the minor side effects and negligible pharmacological interactions with other drugs, it is conceivable that an adjuvant or combinatorial therapy with 1,8-Cineol for respiratory diseases caused by corona- or influenza viruses would be beneficial.

2.
Cell Death Dis ; 15(7): 517, 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-39030166

ABSTRACT

Head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease, and death rates have remained at approximately 50% for decades. New tumor-targeting strategies are desperately needed, and a previous report indicated the triggered differentiation of HPV-negative HNSCC cells to confer therapeutic benefits. Using patient-derived tumor cells, we created a similar HNSCC differentiation model of HPV+ tumor cells from two patients. We observed a loss of malignant characteristics in differentiating cell culture conditions, including irregularly enlarged cell morphology, cell cycle arrest with downregulation of Ki67, and reduced cell viability. RNA-Seq showed myocyte-like differentiation with upregulation of markers of myofibril assembly. Immunofluorescence staining of differentiated and undifferentiated primary HPV+ HNSCC cells confirmed an upregulation of these markers and the formation of parallel actin fibers reminiscent of myoblast-lineage cells. Moreover, immunofluorescence of HPV+ tumor tissue revealed areas of cells co-expressing the identified markers of myofibril assembly, HPV surrogate marker p16, and stress-associated basal keratinocyte marker KRT17, indicating that the observed myocyte-like in vitro differentiation occurs in human tissue. We are the first to report that carcinoma cells can undergo a triggered myocyte-like differentiation, and our study suggests that the targeted differentiation of HPV+ HNSCCs might be therapeutically valuable.


Subject(s)
Cell Differentiation , Cell Survival , Head and Neck Neoplasms , Squamous Cell Carcinoma of Head and Neck , Humans , Squamous Cell Carcinoma of Head and Neck/virology , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/metabolism , Head and Neck Neoplasms/virology , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/metabolism , Papillomavirus Infections/virology , Papillomavirus Infections/pathology , Papillomavirus Infections/metabolism , Cell Lineage , Muscle Cells/virology , Muscle Cells/metabolism , Muscle Cells/pathology , Papillomaviridae/physiology , Cell Line, Tumor , Human Papillomavirus Viruses
3.
Sci Rep ; 14(1): 4061, 2024 02 19.
Article in English | MEDLINE | ID: mdl-38374370

ABSTRACT

Molecular diagnostics is an increasingly important clinical tool, especially in routine sampling. We evaluated two non-invasive methods (oral swabs and mouthwashes) for sampling nucleic acids from the oral/pharyngeal area. We created a workflow from sample collection (n = 59) to RT-qPCR based analysis. The samples were further characterized in terms of their cellular composition as well as the purity, degradation and microbial content of the derived DNA/RNA. We determined the optimal housekeeping genes applicable for these types of samples. The cellular composition indicated that mouthwashes contained more immune cells and bacteria. Even though the protocol was not specifically optimized to extract bacterial RNA it was possible to derive microbial RNA, from both sampling methods. Optimizing the protocol allowed us to generate stable quantities of DNA/RNA. DNA/RNA purity parameters were not significantly different between the two sampling methods. Even though integrity analysis demonstrated a high level of degradation of RNA, corresponding parameters confirmed their sequencing potential. RT-qPCR analysis determined TATA-Box Binding Protein as the most favorable housekeeping gene. In summary, we have developed a robust method suitable for multiple downstream diagnostic techniques. This protocol can be used as a foundation for further research endeavors focusing on developing molecular diagnostics for the oropharyngeal cavity.


Subject(s)
Nucleic Acids , Nucleic Acids/genetics , Mouthwashes , Pathology, Molecular , RNA/genetics , DNA
4.
Audiol Neurootol ; 29(3): 246-252, 2024.
Article in English | MEDLINE | ID: mdl-38325346

ABSTRACT

INTRODUCTION: Surgical treatment of Ménière's disease (MD) and deafness aims to treat vertigo and hearing disabilities. Current treatment options like labyrinthectomy and cochlear implantation (CI) have shown acceptable results but are destructive. Less destructive procedures, like the occlusion of the lateral semicircular canal and endolymphatic sac surgery, have been shown to be successful in vertigo control. The combination of both procedures with CI has not been investigated; therefore the objective of this study was to investigate the outcome of this combination in patients with single-sided MD and moderately severe to complete sensorineural hearing loss. METHODS: In this retrospective study, 10 patients with single-sided MD and moderately severe to complete sensorineural hearing loss were included. In all of them, a single-staged surgery, which consisted of CI, endolymphatic sac surgery, and occlusion of the lateral semicircular canal, was performed. The surgery was performed after a failed conservative therapy trial. The clinical outcome was evaluated by the Dizziness Handicap Inventory (DHI) and audiological tests. These were assessed preoperatively, 3 and 6 months after surgery. An MRI with a hydrops sequence was performed to support the clinical diagnosis. RESULTS: After the combined surgery, the mean DHI testing improved significantly from 71 to 30. Mean audiological monosyllabic speech testing outcome with the cochlea implant was 65% at 65 dB. The residual hearing of 2 patients could be preserved after the surgical procedure. CONCLUSION: The combination of occlusion of the lateral semicircular canal, endolymphatic sac surgery, and CI is an efficient low traumatic treatment for patients with a single-sided MD and moderately severe to complete sensorineural hearing loss.


Subject(s)
Cochlear Implantation , Endolymphatic Sac , Hearing Loss, Sensorineural , Meniere Disease , Semicircular Canals , Humans , Meniere Disease/surgery , Male , Middle Aged , Retrospective Studies , Female , Semicircular Canals/surgery , Endolymphatic Sac/surgery , Adult , Aged , Hearing Loss, Sensorineural/surgery , Treatment Outcome , Deafness/surgery
5.
HNO ; 72(7): 515-519, 2024 Jul.
Article in German | MEDLINE | ID: mdl-38180478

ABSTRACT

More than 5% of the world's population suffers from disabling hearing loss. If the cause of hearing loss is unclear, it is referred to as idiopathic sudden sensorineural hearing loss (ISSNHL). After failure of standard treatment, the use of hearing aids or a cochlear implant is generally recommended. In this case, a 55-year-old patient was treated with cochlear implantation (CI) after ISSNHL and unsuccessful conservative therapy. Approximately 1 year after implantation and 7 years after the sudden hearing loss, subjective measurements revealed restoration of the hearing threshold.


Subject(s)
Auditory Threshold , Cochlear Implants , Humans , Middle Aged , Treatment Outcome , Male , Hearing Loss, Sensorineural/therapy , Hearing Loss, Sensorineural/surgery , Cochlear Implantation , Hearing Loss, Sudden/therapy , Female
6.
Eur Arch Otorhinolaryngol ; 281(4): 1693-1700, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37847285

ABSTRACT

PURPOSE: This study retrospectively evaluated the efficacy and versatility of reopening procedures for the permanent occlusion of the cartilaginous Eustachian tube (POET) by analyzing four consecutive cases. METHODS: The study included all patients diagnosed with POET who suffered from Eustachian tube occlusion and glue ear. A combined approach of endoscopic transnasal/transoral laser surgery was utilized to reopen the POET. This was subsequently followed by balloon dilation (BET) and stenting for a duration of six weeks. In one distinct case, the Eustachian tube orifice was approached via a transtympanic method, where a balloon catheter was placed. The primary outcome measures targeted the success rate of reopening, which was quantified using audiological outcomes and Eustachian tube patency verified by a positive Valsalva maneuver. RESULTS: Four patients, with an age range of 14-62 years (mean age of 29.3 years), were subject to Eustachian tube reopening. The duration of follow-up varied between 10 and 24 months, averaging at 16.2 months. Notably, 75% of the surgically treated ears displayed no evidence of glue ear upon their last follow-up and showed restoration of Eustachian tube patency. The procedures were executed without any surgical complications. The causes for POET in these patients were heterogeneous: two were attributed to scarring post adenoidectomy, one to occlusion following orthognathic surgery and the remaining one due to prior radiotherapy treatment for squamous cell carcinoma located at the soft palate. DISCUSSION: Total occlusion of the cartilaginous Eustachian tube may be linked to persistent middle ear diseases. It is imperative to conduct nasopharyngeal endoscopy in these cases. The findings from this study suggest that the Eustachian tube reopening procedure is predominantly effective and safe for patients with POET stemming from a variety of pathologies. Future research should focus on exploring advanced stenting devices and necessitate longer follow-up periods for comprehensive understanding.


Subject(s)
Ear Diseases , Eustachian Tube , Laser Therapy , Otitis Media , Humans , Adult , Adolescent , Young Adult , Middle Aged , Eustachian Tube/surgery , Eustachian Tube/pathology , Retrospective Studies , Ear Diseases/surgery , Otitis Media/surgery , Laser Therapy/methods , Dilatation/methods , Treatment Outcome
7.
Biomed Pharmacother ; 167: 115518, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37717534

ABSTRACT

Head and neck squamous cell carcinoma present a high mortality rate. Melatonin has been shown to have oncostatic effects in different types of cancers. However, inconsistent results have been reported for in vivo applications. Consequently, an alternative administration route is needed to improve bioavailability and establish the optimal dosage of melatonin for cancer treatment. On the other hand, the use of patient-derived tumor models has transformed the field of drug research because they reflect the heterogeneity of patient tumor tissues. In the present study, we explore mechanisms for increasing melatonin bioavailability in tumors and investigate its potential as an adjuvant to improve the therapeutic efficacy of cisplatin in the setting of both xenotransplanted cell lines and primary human HNSCC. We analyzed the effect of two different formulations of melatonin administered subcutaneously or intratumorally in Cal-27 and SCC-9 xenografts and in patient-derived xenografts. Melatonin effects on tumor mitochondrial metabolism was also evaluated as well as melatonin actions on tumor cell migration. In contrast to the results obtained with the subcutaneous melatonin, intratumoral injection of melatonin drastically inhibited tumor progression in HNSCC-derived xenografts, as well as in patient-derived xenografts. Interestingly, intratumoral injection of melatonin potentiated CDDP effects, decreasing Cal-27 tumor growth. We demonstrated that melatonin increases ROS production and apoptosis in tumors, targeting mitochondria. Melatonin also reduces migration capacities and metastasis markers. These results illustrate the great clinical potential of intratumoral melatonin treatment and encourage a future clinical trial in cancer patients to establish a proper clinical melatonin treatment.


Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Melatonin , Humans , Squamous Cell Carcinoma of Head and Neck/drug therapy , Melatonin/pharmacology , Melatonin/therapeutic use , Carcinoma, Squamous Cell/pathology , Heterografts , Injections, Intralesional , Head and Neck Neoplasms/drug therapy , Cisplatin/pharmacology , Cisplatin/therapeutic use , Cell Line, Tumor , Oxidative Stress
9.
Brain Sci ; 13(6)2023 May 25.
Article in English | MEDLINE | ID: mdl-37371333

ABSTRACT

INTRODUCTION: Cochlear implantation in patients with Ménière's disease (MD) is the treatment of choice in cases of functional deafness. Additional vertigo control is of central importance in this group of patients. Endolymphatic hydrops (ELH) is the pathophysiological correlate of MD and can be evaluated by magnet resonance imaging (MRI). Bilateral MD occurs in 10-33% and can be the reason for a postoperative persisting or newly occurring vertigo in this group. Recent developments in the field of implant magnets and experience in MRI sequences allow the diagnostic performance of MRI in cochlear implantees to be evaluated. The aim of the present study was to evaluate the possibility of MRI as a visual diagnostic tool for endolymphatic hydrops in cochlear implantees. MATERIAL AND METHODS: This was a retrospective study including three cochlear implantees (age: 61-76 years, one female, two male) suffering from MD who, postoperatively, had a recurrence of vertigo with Ménière's-like symptoms. An MRI was performed for the evaluation of ELH (ELH-MRI). MRI observation was performed by a 4 h iv. delayed Gad 3 D Flair sequence. RESULTS: In all cases, the ipsilateral implant magnet artifact covered the vestibulum, the semicircular canals and the cochlea. The contralateral vestibulum, the semicircular canal and the cochlea were fully observable, and a classification of the ELH-MRI could be performed. CONCLUSION: ELH-MRI scanning allows for the detection of contralateral labyrinthine endolymphatic hydrops and is a tool for the postoperative evaluation of vertigo in cochlear implantees.

10.
Front Surg ; 10: 1195473, 2023.
Article in English | MEDLINE | ID: mdl-37188097

ABSTRACT

[This corrects the article DOI: 10.3389/fsurg.2023.1077407.].

11.
NPJ Vaccines ; 8(1): 49, 2023 Apr 01.
Article in English | MEDLINE | ID: mdl-37005390

ABSTRACT

Recurrent Respiratory Papillomatosis(RRP) is a rare disease with severe morbidity. Treatment is surgical. Prevailing viewpoint is that prophylactic HPV vaccines do not have therapeutic benefit due to their modus operandi. Studies on HPV vaccination alongside surgery were meta-analysed to test effect on burden of disease. Databases were accessed Nov and Dec 2021 [PubMed, Cochrane, Embase and Web of Science]. Main outcome measured was: Mean paired differences in the number of surgeries or recurrences per month. Analyses was performed using: Random effect maximal likelihood estimation model using the Stata module Mataan(StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX:StataCorp LLC.) Our results found n = 38 patients, suitable for syntheses with one previous meta-analyses (4 published, 2 unpublished studies) n = 63, total of n = 101 patients. Analyses rendered an overall reduction of 0.123 recurrences or surgeries per month (95% confidence interval [0.064, 0.183]). Our meta-analyses concludes that HPV vaccine is a beneficial adjunct therapy alongside surgery.

12.
BMC Cancer ; 23(1): 47, 2023 Jan 13.
Article in English | MEDLINE | ID: mdl-36639629

ABSTRACT

BACKGROUND: New concepts for a more effective anti-cancer therapy are urgently needed. Experimental flaws represent a major counter player of this development and lead to inaccurate and unreproducible data as well as unsuccessful translation of research approaches into clinics. In a previous study we have created epithelial cell cultures from head and neck squamous cell carcinoma (HNSCC) tissue. METHODS: We characterize primary cell populations isolated from human papillomavirus positive HNSCC tissue for their marker expression by RT-qPCR, flow cytometry, and immunofluorescence staining. Their sensitivity to MDM2-inhibition was measured using cell viability assays. RESULTS: Primary HNSCC cell cultures showed the delayed formation of spheroids at higher passages. These spheroids mimicked the morphology and growth characteristics of other established HNSCC spheroid models. However, expression of epithelial and mesenchymal markers could not be detected in these cells despite the presence of the HNSCC stem cell marker aldehyde dehydrogenase 1 family member A1. Instead, strong expression of B- and T-lymphocytes markers was observed. Flow cytometry analysis revealed a heterogeneous mixture of CD3 + /CD25 + T-lymphocytes and CD19 + B-lymphocytes at a ratio of 4:1 at passage 5 and transformed lymphocytes at late passages (≥ passage 12) with CD45 + CD19 + CD20 + , of which around 10 to 20% were CD3 + CD25 + CD56 + . Interestingly, the whole population was FOXP3-positive indicative of regulatory B-cells (Bregs). Expression of transcripts specific for the Epstein-Barr-virus (EBV) was detected to increase in these spheroid cells along late passages, and this population was vulnerable to MDM2 inhibition. HPV + HNSCC cells but not EBV + lymphocytes were detected to engraft into immunodeficient mice. CONCLUSIONS: In this study we present a primary cell culture of EBV-infected tumor-infiltrating B-lymphocytes, which could be used to study the role of these cells in tumor biology in future research projects. Moreover, by describing the detailed characteristics of these cells, we aim to caution other researchers in the HNSCC field to test for EBV-infected lymphocyte contaminations in primary cell cultures ahead of further experiments. Especially researchers who are interested in TIL-based adopted immunotherapy should exclude these cells in their primary tumor models, e.g. by MDM2-inhibitor treatment. BI-12-derived xenograft tumors represent a suitable model for in vivo targeting studies.


Subject(s)
Epstein-Barr Virus Infections , Head and Neck Neoplasms , Humans , Mice , Animals , Squamous Cell Carcinoma of Head and Neck , Herpesvirus 4, Human , Lymphocytes , Cell Proliferation , Cell Culture Techniques
13.
J Med Virol ; 95(1): e28254, 2023 01.
Article in English | MEDLINE | ID: mdl-36284485

ABSTRACT

Head and neck cancers are unique in so far that two major oncogenic viruses, Epstein Barr virus (EBV) and Human papillomavirus (HPV) infect adjacent anatomy and cause nasopharyngeal and oropharyngeal cancers, respectively. Dominant recognized carcinogens are alcohol and tobacco but some head and neck cancers have been found to have mixed carcinogens (including betel leaf, areca nuts, slaked lime, viruses, etc.) involved in their oncogenesis and conversely, groups of patients with unknown or less dominant carcinogens involved in their development. These cancers may have had viral involvement in the past but then lost most of their viral nucleic acids (be they DNA and/or RNA) below a detection threshold, thus rendering them virus-negative. Some of these virus-negative tumors appear to have mutagenic signatures associated with virus-positive cancers,  for example, from the APOBEC defense mechanism which is known to mutate viral nucleic acids as well as cause collateral damage to host DNA, with subsequent development of strongly viral prejudiced mutational signatures. These mechanisms are likely to be less efficient at oncogenesis than traditional EBV and HPV oncogenes directly driving mutagenesis, thus accounting for the smaller frequencies of these cancers found. More profound investigations of these unusual tumors are warranted to dissect out these mechanistic pathways.


Subject(s)
Epstein-Barr Virus Infections , Head and Neck Neoplasms , Nucleic Acids , Papillomavirus Infections , Humans , Epstein-Barr Virus Infections/complications , Herpesvirus 4, Human/genetics , Papillomavirus Infections/complications , Head and Neck Neoplasms/genetics , Oncogenic Viruses/genetics , Carcinogenesis , Carcinogens , Papillomaviridae/genetics
14.
Brain Sci ; 12(10)2022 Oct 19.
Article in English | MEDLINE | ID: mdl-36291339

ABSTRACT

INTRODUCTION: The approval process for MRI safety of implants includes physical observations and an experimental evaluation in artificial settings to simulate the in vivo effect. This contains the observation of temperature changes and artificial current generation by the magnetic field. From these findings, the safety of an implant and its effect on the patient can be estimated. MRI safety is based on an in vivo evaluation of adverse events after the approval process, but an actual analysis of the effect on different tissues is not followed. The effect of MRI scanning in cochlea implantees on their residual hearing as the correlate of the hair cell function is so far unknown, therefore the aim of the present study was to observe the effect of 3 T MRI on the residual hearing of cochlea implantees. MATERIAL AND METHODS: In this prospective study, we performed a 3 T MRI T2 2D MS Drive sequence in eight cochlea-implanted ears. Before and after the MRI scan, a bone conduction pure tone audiogram (BC PTA) was performed. All cochlea implantees had a pre-scanning threshold of low frequency residual hearing between 20 dB and 65 dB. RESULTS: Low frequency mean residual hearing was not affected by the 3 T T2 2D MS Drive sequence. We observed a pre-scanning threshold at 250 Hz of 42.9 (SD 3.9) dB and for 500 Hz 57.1 (SD 6.4) dB. Post-scanning BC PTA was for 250 Hz 42.1 (SD 3.9) dB and for 500 Hz 57.1 (SD 5.7) dB. CONCLUSION: 3 T MRI scanning has no significant functional effect on the hair cells in cochlea implantees in low frequencies with a T2 2D MS Drive sequence.

15.
Mol Cancer Ther ; 21(11): 1689-1700, 2022 11 03.
Article in English | MEDLINE | ID: mdl-36099437

ABSTRACT

Loss of the gene SMARCB1 drives the development of malignant rhabdoid tumors, epithelioid sarcomas, and other malignancies. The SMARCB1 protein is a core component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) family of chromatin remodeling complexes, which are important regulators of gene expression and cell differentiation. Here, we use CRISPR-Cas9 to create germline smarcb1 loss of function in zebrafish. We demonstrate that the combination of smarcb1 deficiency with mutant p53 results in the development of epithelioid sarcomas, angiosarcomas, and carcinomas of the thyroid and colon. Although human epithelioid sarcomas do not frequently harbor p53 mutations, smarcb1-deficient tumors in zebrafish were only observed following disruption of p53, indicating that p53 signaling in human tumors might be attenuated through alternative mechanisms, such as MDM2-mediated proteasomal degradation of p53. To leverage this possibility for the treatment of human epithelioid sarcoma, we tested small molecule-mediated disruption of the p53-MDM2 interaction, which stabilized p53 protein leading to p53-pathway reactivation, cell-cycle arrest, and increased apoptosis. Moreover, we found that MDM2 inhibition and the topoisomerase II inhibitor doxorubicin synergize in targeting epithelioid sarcoma cell viability. This could be especially relevant for patients with epithelioid sarcoma because doxorubicin represents the current gold standard for their clinical treatment. Our results therefore warrant reactivating p53 protein in SMARCB1-deficient, p53-wildtype epithelioid sarcomas using combined doxorubicin and MDM2 inhibitor therapy.


Subject(s)
Rhabdoid Tumor , Sarcoma , Animals , Humans , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolism , Zebrafish/metabolism , Tumor Suppressor Protein p53/genetics , DNA-Binding Proteins/metabolism , Chromosomal Proteins, Non-Histone/genetics , Sarcoma/drug therapy , Sarcoma/genetics , Sarcoma/metabolism , Rhabdoid Tumor/genetics , Doxorubicin/pharmacology , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism
16.
Cell Commun Signal ; 20(1): 148, 2022 09 19.
Article in English | MEDLINE | ID: mdl-36123729

ABSTRACT

Middle ear cholesteatoma (MEC), is a destructive, and locally invasive lesion in the middle ear driven by inflammation with an annual incidence of 10 per 100,000. Surgical extraction/excision remains the only treatment strategy available and recurrence is high (up to 40%), therefore developing the first pharmaceutical treatments for MEC is desperately required. This review was targeted at connecting the dysregulated inflammatory network of MEC to pathogenesis and identification of pharmaceutical targets. We summarized the numerous basic research endeavors undertaken over the last 30+ years to identify the key targets in the dysregulated inflammatory pathways and judged the level of evidence for a given target if it was generated by in vitro, in vivo or clinical experiments. MEC pathogenesis was found to be connected to cytokines characteristic for Th1, Th17 and M1 cells. In addition, we found that the inflammation created damage associated molecular patterns (DAMPs), which further promoted inflammation. Similar positive feedback loops have already been described for other Th1/Th17 driven inflammatory diseases (arthritis, Crohn's disease or multiple sclerosis). A wide-ranging search for molecular targeted therapies (MTT) led to the discovery of over a hundred clinically approved drugs already applied in precision medicine. Based on exclusion criteria designed to enable fast translation as well as efficacy, we condensed the numerous MTTs down to 13 top drugs. The review should serve as groundwork for the primary goal, which is to provide potential pharmaceutical therapies to MEC patients for the first time in history. Video Abstract.


Middle ear cholesteatoma (MEC) is a destructive and locally invasive ulcerated lesion in the middle ear driven by inflammation which occurs in 10 out of 100,000 people annually. Surgical extraction/excision is the only treatment strategy available and recurrence is high (up to 40% after ten years), therefore developing the first pharmaceutical treatments for MEC is desperately required. This review is focused on the connections between inflammation and MEC pathogenesis. These connections can be used as attack points for pharmaceuticals. For this we summarized the results of research undertaken over the last 30 + years. MEC pathogenesis can be described by specific inflammatory dysregulation already known from arthritis, Crohn's disease or multiple sclerosis. A hallmark of this dysregulation are positive feedback loops of the inflammation further amplifying itself in a vicious circle-like manner. We have identified over one hundred drugs which are already used in clinic to treat other inflammatory diseases, and could potentially be repurposed to treat MEC. To improve and expedite clinical success rates, we applied certain criteria based on our literature searches and condensed these drugs down to the 13 top drugs. We hope the review will serve as groundwork for the primary goal, which is to provide potential pharmaceutical therapies to MEC patients for the first time in history.


Subject(s)
Cholesteatoma, Middle Ear , Cholesteatoma, Middle Ear/metabolism , Cholesteatoma, Middle Ear/pathology , Cholesteatoma, Middle Ear/surgery , Cytokines , Ear, Middle/metabolism , Ear, Middle/pathology , Humans , Inflammation/pathology
17.
Brain Sci ; 12(5)2022 Apr 29.
Article in English | MEDLINE | ID: mdl-35624970

ABSTRACT

INTRODUCTION: Due to the changes in the indication range for cochlear implants and the demographic development towards an aging society, more and more people are in receipt of cochlear implants. An implantation requires a close-meshed audiological and logopedic aftercare. Hearing therapy rehabilitation currently requires great personnel effort and is time consuming. Hearing and speech therapy rehabilitation can be supported by digital hearing training programs. However, the apps currently on the market are to a limited degree personalized and structured. Increasing digitalization makes it possible, especially in times of pandemics, to decouple hearing therapy treatment from everyday clinical practice. MATERIAL AND METHODS: For this purpose, an app is in development that provides hearing therapy tailored to the patient. The individual factors that influence hearing outcome are considered. Using intelligent algorithms, the app determines the selection of exercises, the level of difficulty and the speed at which the difficulty is increased. RESULTS: The app works autonomously without being connected to local speech therapists. In addition, the app is able to analyze patient difficulties within the exercises and provides conclusions about the need for technical adjustments. CONCLUSIONS: The presented newly developed app represents a possibility to support, replace, expand and improve the classic outpatient hearing and speech therapy after CI implantation. The way the application works allows it to reach more people and provide a time- and cost-saving alternative to traditional therapy.

19.
Curr Oncol Rep ; 24(7): 929-942, 2022 07.
Article in English | MEDLINE | ID: mdl-35347592

ABSTRACT

PURPOSE OF REVIEW: This study assesses the current state of knowledge of head and neck squamous cell carcinomas (HNSCC), which are malignancies arising from the orifices and adjacent mucosae of the aerodigestive tracts. These contiguous anatomical areas are unique in that 2 important human oncoviruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), are causally associated with nasopharyngeal and oropharyngeal cancers, respectively. Mortality rates have remained high over the last 4 decades, and insufficient attention paid to the unique viral and clinical oncology of the different subgroups of HNSCC. RECENT FINDINGS: We have compared and contrasted the 2 double-stranded DNA viruses and the relevant molecular oncogenesis of their respective cancers against other head and neck cancers. Tobacco and alcohol ingestion are also reviewed, as regard the genetic progression/mutation accumulation model of carcinogenesis. The importance of stringent stratification when searching for cancer mutations and biomarkers is discussed. Evidence is presented for a dysplastic/pre-invasive cancerous phase for HPV+ oropharyngeal cancers, and analogous with other HPV+ cancers. This raises the possibility of strategies for cancer screening as early diagnosis will undoubtedly save lives. Staging and prognostication have changed to take into account the distinct biological and prognostic pathways for viral+ and viral- cancers. Diagnosis of pre-cancers and early stage cancers will reduce mortality rates. Multi-modal treatment options for HNSCC are reviewed, especially recent developments with immunotherapies and precision medicine strategies. Knowledge integration of the viral and molecular oncogenic pathways with sound planning, hypothesis generation, and clinical trials will continue to provide therapeutic options in the future.


Subject(s)
Carcinoma, Squamous Cell , Epstein-Barr Virus Infections , Head and Neck Neoplasms , Oropharyngeal Neoplasms , Papillomavirus Infections , Carcinoma, Squamous Cell/pathology , Epstein-Barr Virus Infections/complications , Head and Neck Neoplasms/complications , Head and Neck Neoplasms/therapy , Herpesvirus 4, Human , Humans , Medical Oncology , Papillomaviridae/genetics , Papillomavirus Infections/complications , Papillomavirus Infections/genetics , Squamous Cell Carcinoma of Head and Neck
20.
Audiol Neurootol ; 27(1): 34-39, 2022.
Article in English | MEDLINE | ID: mdl-34130281

ABSTRACT

INTRODUCTION: Intracochlear pressure changes have been assumed to play a central role in hearing preservation during cochlear implantation. The pressure in different settings has been evaluated (temporal bones vs. cochlea models) and was found to have advantages and disadvantages. Experimentally, problems have been discussed to influence the results substantially. OBJECTIVE: The aim of the present study was to evaluate the effect of intracochlear air on the measurements in a cochlea model by using a fiber optic pressure sensor. MATERIALS AND METHODS: The experiments were performed in an uncurled 3D printed full cochlea model. A microfiber-optic pressure sensor was inserted, and intracochlear pressures were evaluated under 3 conditions: (1) cochlea model filled to 100% with fluid, (2) cochlea model filled with air, and (3) cochlea model filled to approximately 50% with fluid. Since the cochlea model is transparent, a direct visualization of air under the microscope was possible when performing the insertions. RESULTS: In the first condition, the mean intracochlear pressure at the end of the insertion was 0.044 psi (SD 0.012, 95% CI). In the second setting, the results were similar. In the last scenario, with 50% filling, the mean intracochlear pressure was statistically significantly different with a mean value of 0.074 psi (SD 0.013, 95% CI) (p < 0.0044, ANOVA). Besides this, in the last condition with 50% fluid, a plateau was formed when the fiber optic reached the air portion. CONCLUSION: The results obtained in a 3D printed full cochlea model show the importance of a direct evaluation of air inside the experimental setting. The exclusion of intracochlear air should be an important factor for the choice of the model for intracochlear pressure measurement (temporal bone vs. cochlea model).


Subject(s)
Cochlear Implantation , Cochlear Implants , Cochlea/surgery , Cochlear Implantation/methods , Hearing , Pressure
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