Combined balloon Eustachian tuboplasty/endoscopic sinus surgery for patients with chronic rhinosinusitis and Eustachian tube dysfunction.

BACKGROUND: To elucidate the role of balloon Eustachian tuboplasty (BET) in the management of chronic rhinosinusitis with obstructive Eustachian tube dysfunction (ETD), we evaluated the results of endoscopic sinus surgery (ESS) with and without BET in patients with chronic rhinosinusitis with obstructive ETD. METHODS: This randomized controlled trial conducted in a single-institution tertiary care center setting included 50 patients diagnosed with primary chronic rhinosinusitis and obstructive ETD between July 2018 and June 2022. Twenty-five patients were prospectively enrolled for combined ESS/BET. The control group (25 patients) underwent ESS alone. Outcome measurements of the Sinonasal Outcome Test 22, modified Lund-Kennedy score, Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7), and serial Eustachian tube function test results were analyzed 3 months postoperatively. RESULTS: The improvement (12.60 ± 6.50) in the ETDQ-7 score in the BET group was significantly higher than that in the control group (6.60 ± 5.58). The ratio of improvement in the ETDQ-7 score was also significantly higher in the BET than in the control group (92% vs. 68%, p = 0.034). Logistic regression analysis showed that performing BET (odds ratio [OR]: 5.41, 95% confidence interval [CI]: 1.02-28.79, p = 0.048) and a low post-modified Lund-Kennedy score (OR: 0.15, 95% CI: 0.04-0.54, p = 0.004) were significantly associated with ETDQ-7 score improvement. CONCLUSION: Combined BET/ESS could decrease otologic symptoms and improve Eustachian tube function. BET may be an appropriate adjunctive procedure for treating chronic rhinosinusitis with obstructive ETD.

Otoprotection against aminoglycoside- and cisplatin-induced ototoxicity focusing on the upstream drug uptake pathway.

Aminoglycoside- and cisplatin-induced ototoxicity, which is a significant issue owing to the widespread use of these drugs in clinical practice, involves the entry of aminoglycosides and cisplatin into the endolymph and hair cells via specific channels or transporters, followed by reactive oxygen species (ROS) generation and hair cells apoptosis. Current strategies focalize primarily on interference with downstream ROS effects; however, recent evidence has demonstrated that inhibiting the uptake of aminoglycosides and cisplatin by hair cells is another promising strategy for tackling the upstream drug uptake pathway. With advances in structural biology, the conformations of certain aminoglycoside and cisplatin channels and transporters, such as the mechanoelectrical transduction channel and organic cation transporter-2, have been largely elucidated. These channels and transporters may become potential targets for the introduction of new otoprotective strategies. This review focuses on the strategies for inhibiting ototoxic drugs uptake by auditory hair cells and provides potential targets for recent developments in the field of otoprotection. Molecular dynamics (MD) simulations of these proteins could help identify the molecules that inhibit the uptake of aminoglycosides and cisplatin by hair cells. Integrating upstream drug uptake pathway targets and MD simulations may help dissect molecular mechanisms and develop novel otoprotective strategies for aminoglycoside- and cisplatin-induced ototoxicity.

Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women.

INTRODUCTION: Variants in the tau gene (MAPT) region are associated with breast cancer in women and Alzheimer's disease (AD) among persons lacking apolipoprotein E ε4 (ε4-). METHODS: To identify novel genes associated with tau-related pathology, we conducted two genome-wide association studies (GWAS) for AD, one among 10,340 ε4- women in the Alzheimer's Disease Genetics Consortium (ADGC) and another in 31 members (22 women) of a consanguineous Hutterite kindred. RESULTS: We identified novel associations of AD with MGMT variants in the ADGC (rs12775171, odds ratio [OR] = 1.4, P = 4.9 × 10-8 ) and Hutterite (rs12256016 and rs2803456, OR = 2.0, P = 1.9 × 10-14 ) datasets. Multi-omics analyses showed that the most significant and largest number of associations among the single nucleotide polymorphisms (SNPs), DNA-methylated CpGs, MGMT expression, and AD-related neuropathological traits were observed among women. Furthermore, promoter capture Hi-C analyses revealed long-range interactions of the MGMT promoter with MGMT SNPs and CpG sites. DISCUSSION: These findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women.

Curcuminoids Inhibit Angiogenic Behaviors of Human Umbilical Vein Endothelial Cells via Endoglin/Smad1 Signaling.

BACKGROUND: Angiogenesis is primarily attributed to the excessive proliferation and migration of endothelial cells. Targeting the vascular endothelial growth factor (VEGF) is therefore significant in anti-angiogenic therapy. Although these treatments have not reached clinical expectations, the upregulation of alternative angiogenic pathways (endoglin/Smad1) may play a critical role in drug (VEGF-neutralizing agents) resistance. Enhanced endoglin expression following a VEGF-neutralizing therapy (semaxanib®) was noted in patients. Treatment with an endoglin-targeting antibody augmented VEGF expression in human umbilical vein endothelial cells (HUVECs). Therefore, approaches that inhibit both the androgen and VEGF pathways enhance the HUVECs cytotoxicity and reverse semaxanib resistance. The purpose of this study was to find natural-occurring compounds that inhibited the endoglin-targeting pathway. METHODS: Curcuminoids targeting endoglin were recognized from two thousand compounds in the Traditional Chinese Medicine Database@Taiwan (TCM Database@Taiwan) using Discovery Studio 4.5. RESULTS: Our results, obtained using cytotoxicity, migration/invasion, and flow cytometry assays, showed that curcumin (Cur) and demethoxycurcumin (DMC) reduced angiogenesis. In addition, Cur and DMC downregulated endoglin/pSmad1 phosphorylation. CONCLUSIONS: The study first showed that Cur and DMC demonstrated antiangiogenic activity via the inhibition of endoglin/Smad1 signaling. Synergistic effects of curcuminoids (i.e., curcumin and DMC) and semaxanib on HUVECs were found. This might be attributed to endoglin/pSmad1 downregulation in HUVECs. Combination treatment with curcuminoids and a semaxanib is therefore expected to reverse semaxanib resistance.

Effect of Round Window Opening Size on Residual Hearing Preservation in Cochlear Implantation.

OBJECTIVES: This study aims to compare the hearing preservation outcomes in cochlear implant surgery following slit versus full opening of the round window membrane. SETTING: Tertiary referral center. STUDY DESIGN: Comparative study. SUBJECTS AND METHODS: Seventy patients (mean, 26.3 years; range, 2-69 years) who underwent cochlear implantation via the round window approach were included in the study. Thirty-five subjects were prospectively enrolled for cochlear implantation via the open round window technique between August 2018 and January 2019. Thirty-five patients who underwent cochlear implantation from January 2017 to July 2018 via the slit round window opening, frequency matched by sex and age, were retrospectively enrolled. Pre- and postoperative thresholds were obtained. The percentage of hearing preservation was computed with the HEARRING Network formula and classified into complete, partial, and minimal hearing preservation. The results between the groups were compared and analyzed at 6 months postoperatively. RESULTS: The rate of complete hearing preservation in the open group was statistically significant (P = .030) at 71.4% (n = 25) as compared with 45.7% (n = 16) in the slit group. CONCLUSIONS: The widely opened round window may be an optional technique that surgeons can utilize to improve hearing preservation outcomes.

Comparison of Hearing Preservation Outcomes Using Extended Versus Single-Dose Steroid Therapy in Cochlear Implantation.

OBJECTIVES: The purpose of this study was to compare the hearing preservation outcomes of patients who received extended versus single-dose steroid therapy in cochlear implant surgery. DESIGN: Case-control. SETTING: Tertiary referral centers in Taiwan from April 2017 to 2019. PARTICIPANTS: A total of 70 patients aged 1 to 78 years old (mean = 18.04, standard deviation [SD] = 21.51) who received cochlear implantation via the round window approach were included in the study. Prospectively, 35 cases were enrolled for cochlear implantation with single-dose therapy. Thirty-five controls who underwent cochlear implantation with extended therapy were retrospectively enrolled after frequency matching. OUTCOME MEASURES: The main outcome measure was the rate of hearing preservation. This was calculated based on the HEARRING Network formula and results were categorized as complete, partial, and minimal. Impedances served as secondary outcomes. RESULTS: There was no significant difference in the complete hearing preservation rates between the extended and single-dose groups at 6 months postoperatively. Impedances were significantly lower in the extended group after 1 month and 6 months of follow up. When the complete and partial hearing preservation groups were compared, the size of round window opening and speed of insertion were found to be statistically significant. CONCLUSIONS: Both extended and single-dose therapies result in good hearing preservation in patients who undergo cochlear implantation. However, better impedances can be expected from patients who received extended therapy. A slower speed of insertion and a widely opened round window play a role in hearing preservation.

Off-Target V(D)J Recombination Drives Lymphomagenesis and Is Escalated by Loss of the Rag2 C Terminus.

Genome-wide analysis of thymic lymphomas from Tp53(-/-) mice with wild-type or C-terminally truncated Rag2 revealed numerous off-target, RAG-mediated DNA rearrangements. A significantly higher fraction of these errors mutated known and suspected oncogenes/tumor suppressor genes than did sporadic rearrangements (p < 0.0001). This tractable mouse model recapitulates recent findings in human pre-B ALL and allows comparison of wild-type and mutant RAG2. Recurrent, RAG-mediated deletions affected Notch1, Pten, Ikzf1, Jak1, Phlda1, Trat1, and Agpat9. Rag2 truncation substantially increased the frequency of off-target V(D)J recombination. The data suggest that interactions between Rag2 and a specific chromatin modification, H3K4me3, support V(D)J recombination fidelity. Oncogenic effects of off-target rearrangements created by this highly regulated recombinase may need to be considered in design of site-specific nucleases engineered for genome modification.

A rapid and accurate technique for the identification of the recurrent laryngeal nerve.

OBJECTIVE: We studied the anatomic relationship between the recurrent laryngeal nerve (RLN) and the third tracheal ring, which was very important for rapid identification of RLN in our hands. METHODS: This study was initially performed using 8 fresh cadavers (4 female and 4 male). The transverse nerve location from the third trachea and the depth from its anterior surface were measured. We further observed the topography of RLN in relation to the trachea in 60 patients, between November 2008 and January 2011, at the Tri-Service General Hospital and Buddhist Tzu Chi General Hospital, Taipei Branch, Taiwan, with 46 lobo-isthmectomies and 14 total thyroidectomies. The time spent in identifying the RLN was also recorded. RESULTS: Among cadaver groups, the transverse distance (width) and the vertical distance (depth) averaged 3.3 and 17.6 mm, respectively. Among the clinical cases, the width and depth averaged 4.4 and 14.6 mm, respectively. The depth measured in males was significantly deeper than that in females (22.3 vs 13.2 mm) (P < .05). The time spent in identifying the RLN after starting dissection in the RLN triangle was not statistically significantly different between the cadaver group and the clinical group (10.6 ± 5.7 seconds and 15.5 ± 17.7 seconds, respectively; P > .05). The median time was 9 and 10 seconds, respectively. There was no statistically significant side-to-side difference in terms of the time spent in searching for the RLN. CONCLUSION: Using the third ring as guidance, our inferior-superior technique offers an extra benefit in identifying the RLN safely and quickly, as compared to the conventional inferior approach.

Using multi-stimulus auditory steady state response to predict hearing thresholds in high-risk infants.

The purpose of this study was to investigate whether multi-stimulus auditory steady-state responses were capable of estimating hearing thresholds in high-risk infants. A retrospective chart review study. Three tertiary referral centers. Infants born between January 2004 and December 2006 who met the criteria for risk factors of congenital hearing loss were enrolled in the study. While under sedation, the multi-stimulus auditory steady-state response was used to determine multi-channel auditory steady-state response thresholds for high-risk infants younger than 13 months. Conditioned play audiometry was then applied to these children at 23-48 months of age to obtain pure tone audiograms. Auditory steady-state response thresholds and pure tone thresholds were then compared. A total of 249 high-risk infants were enrolled in the study. 39 infants were lost during follow-up. The remaining 216 infants completed both examinations. The Pearson correlation coefficients (r) between the ASSR levels and pure tone thresholds were 0.88, 0.94, 0.94 and 0.97 at 500, 1,000, 2,000 and 4,000 Hz, respectively. The strength of the relationship between the auditory steady-state responses and pure tone thresholds increased with more severe degrees of hearing loss and higher frequencies. We conclude that initial multichannel ASSR thresholds measured under sedation are highly correlated with pure tone thresholds obtained 2 or 3 years later. ASSR can be used to predict the frequency-specific hearing thresholds of high-risk infants and can provide information for early hearing intervention.

TTK/hMps1 participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on threonine 68.

CHK2/hCds1 plays important roles in the DNA damage-induced cell cycle checkpoint by phosphorylating several important targets, such as Cdc25 and p53. To obtain a better understanding of the CHK2 signaling pathway, we have carried out a yeast two-hybrid screen to search for potential CHK2-interacting proteins. Here, we report the identification of the mitotic checkpoint kinase, TTK/hMps1, as a novel CHK2-interacting protein. TTK/hMps1 directly phosphorylates CHK2 on Thr-68 in vitro. Expression of a TTK kinase-dead mutant, TTK(D647A), interferes with the G(2)/M arrest induced by either ionizing radiation or UV light. Interestingly, induction of CHK2 Thr-68 phosphorylation and of several downstream events, such as cyclin B1 accumulation and Cdc2 Tyr-15 phosphorylation, is also affected. Furthermore, ablation of TTK expression using small interfering RNA results not only in reduced CHK2 Thr-68 phosphorylation, but also in impaired growth arrest. Our results are consistent with a model in which TTK functions upstream from CHK2 in response to DNA damage and suggest possible cross-talk between the spindle assembly checkpoint and the DNA damage checkpoint.