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CONCLUSIONS: The precise risk factors for neurological complications after acoustic neurinoma radiosurgery were identified on long-term follow-up. Type 2 neurofibromatosis was found to be a risk factor for hearing loss and peripheral tumor dose was a risk factor for seventh and fifth cranial nerve injuries. These risk factors corresponded to those reported at other institutions. At the present time, controversy exists regarding history of prior surgical resection and tumor size as risk factors for cranial nerve complications. OBJECTIVES: To identify more precisely the risk factors for neurological complications after stereotactic radiosurgery (SRS) based on long-term follow-up. PATIENTS AND METHODS: Between June 1990 and September 1998, 138 patients with acoustic neurinomas had SRS at Tokyo University Hospital. Of these, the 125 patients who were followed up for at least 6 months were entered into the present study. The patients' ages ranged from 13 to 77 years (median 53 years). The average tumor diameter ranged from 6.7 to 25.4 mm (mean 13.9 mm). The maximum tumor doses ranged from 20 to 40 Gy (mean 29.8 Gy), and the peripheral doses ranged from 12 to 25 Gy (mean 15.4 Gy). One to 12 isocenters were used (median 4). The follow-up period ranged from 6 to 191 months (median 60 months). The potential risk factors for neurological complications were analyzed using two univariate actuarial analyses. The neurological complications studied included hearing loss, facial palsy, and trigeminal nerve dysfunction. The variables analyzed were age, gender, prior operation, neurofibromatosis type 2 (NF2), tumor diameter, maximum tumor dose, peripheral tumor irradiation dose, and the number of isocenters. Variables with significant p values (<0.05) on both actuarial analyses were considered risk factors. RESULTS: NF2 was significantly correlated with both total hearing loss and pure tone threshold (PTA) elevation; a history of prior surgical resection, tumor size, and the peripheral tumor dose were significantly correlated with facial palsy; and the peripheral tumor dose was significantly correlated with trigeminal neuropathy. [ABSTRACT FROM AUTHOR]

CONCLUSIONS: The results of a series of studies including the present study suggest that acute dysfunction of the utricular afferents accompanied by acute dysfunction of the saccular afferents might require more time for the compensation of the otolith-ocular system than acute utricular dysfunction that was not accompanied by acute saccular dysfunction. Perhaps the inputs from the saccule also have some contribution to the subjective visual horizontal (SVH). OBJECTIVE: To clarify if acute dysfunction of the saccular afferents affects the SVH. PATIENTS AND METHODS: Twenty-six patients with vestibular neurolabyrinthitis (20 men and 6 women, 23-67 years of age) were enrolled in this study. They had undergone measurement of SVH at the early stage (within 1 month after the attack) and 3 months after the attack. For the measurement of SVH, we used a device that has a red bar of light-emitting diodes with a head fixing frame. They also underwent vestibular evoked myogenic potentials (VEMPs) testing. For the recording of VEMPs, 95 dBnHL clicks were presented. RESULTS: Patients with vestibular neurolabyrinthitis showed deviation of SVH toward the affected side-down at the early stage after the attack, irrespective of VEMP results. However, 3 months after the attack SVH was significantly more deviated toward the affected side-down in patients who showed absent VEMPs than those with VEMPs present (p<0.01 Mann-Whitney U test). [ABSTRACT FROM AUTHOR]

CONCLUSION: Lomerizine, a calcium channel blocker, may be effective as a treatment for migraine-associated vertigo (MAV). Objective. To determine the clinical characteristics of patients with MAV in Japan and the effectiveness of lomerizine. PATIENTS AND METHODS: This was a retrospective chart review carried out in a university hospital of 33 patients who fulfilled the diagnostic criteria for MAV. All patients were initially treated with dietary manipulation. If this therapy was unsuccessful, oral medications, mainly lomerizine, were administered. Medical records were reviewed to find clinical characteristics of patients with MAV and to evaluate the effects of the therapy on vertigo/dizziness symptoms. RESULTS: A marked female predominance was found (23 women, 10 men). The frequency and the duration of vertigo varied across patients. About 60% of the patients had cochlear symptoms during an attack, among which bilateral aural fullness was most frequent. Oto-neurological examination showed abnormalities in 33% of the patients. Overall, 27 of the 33 patients (82%) responded to our therapy. Among the 22 patients who were prescribed lomerizine, 19 patients (87%) showed resolution or significant improvement of the symptoms. [ABSTRACT FROM AUTHOR]

Objective: Our goal was to clarify the clinical significance of vibration-induced nystagmus (VIN).Methods: One hundred patients with unilateral vestibulocochlear disorders were enrolled into this study. However, patients with spontaneous nystagmus were excluded. Vibratory stimuli (approximately 100 Hz) were presented to the mastoids and the forehead. Patients also underwent caloric testing and vestibular evoked myogenic potential testing.Results: Of the 100 patients, 60 (60%) showed VIN. The nystagmus was mainly horizontal. VIN was more frequently evoked on the mastoids than the forehead. In the majority of patients, the direction of VIN was toward the healthy side, whereas some patients, especially patients with Meniere's disease, showed nystagmus toward the affected side. VIN was frequently evoked in patients with severe unilateral vestibular damages (canal paresis >50%) (39 of 43, or 90%).Conclusion: VIN testing is a simple and sensitive clinical test that indicates unilateral vestibular dysfunction. [ABSTRACT FROM AUTHOR]

A new experimental device was developed to observe and measure dynamical generations of supercritical CO2 in a chamber. Temperature and pressure were measured locally by thin thermocouple and pressure transducer. The Rayleigh scattering in the chamber was visualized by a high-speed video camera. Heating of the liquid CO2 was conducted by a ceramic heater from the upper or the lower side of the chamber. In the case of heating from the upper side, temperature profile was stable and generates scCO2 slowly within a few seconds. On the other hand, in the case of heating from the lower side, scCO2 was created faster within a second but natural convection and turbulence were observed. Numerical simulations of the scCO2 creation in a chamber were also performed using the COMSOL Multiphysics with a program package for themophysical properties of CO2 called the PROPATH. It showed that scCO2 creation in the heating from the upper side was stable due to the gas-like properties of the scCO2 near the heater. In the case of heating from the lower side, density distribution depended on temperature distribution firstly but after natural convection grows, flow in the chamber became disturbed and the density distribution depended not only on temperature distribution but also on the density fluctuation caused by the convection vortexes. Same tendency was observed in experimental results.

Objective --To study nystagmus-sensation dissociation (NSD), i.e. caloric nystagmus without the sensation of vertigo, in patients with spinocerebellar degeneration (SCD). Material and Methods --The neuro-otological and neuro-radiological records of 179 patients clinically diagnosed as having SCD (91 males, 88 females; age range 20-89 years) and 48 patients diagnosed as having peripheral vestibular disorders (15 males, 33 females; age range 21-80 years) were reviewed. Subjects underwent caloric tests using cold water (20°C) in a totally dark room. Immediately after each test session, subjects were asked if they had experienced spinning or moving sensations during the test. Maximum slow phase eye velocities (SPEVs) were measured using electronystagmography. Results --Among patients with peripheral vestibular disorders, all patients with SPEVs >15°/s experienced spinning or moving sensations during testing. Among the 179 patients with SCD, 21 (39 sides) showed maximum SPEVs >15°/s without spinning or moving sensations. In particular, 8 patients (10 sides) had maximum SPEVs >25°/s without spinning or moving sensations. Common lesions in the cerebral cortex could not be detected using either MRI or single-photon emission CT. Conclusion --Patients with SCD may also have NSD, which may be attributable to subcortical lesions in the ascending pathways to the vestibular cortex. [ABSTRACT FROM AUTHOR]

Introduction: It is unknown whether prodromal dizziness (PD) before an attack of vestibular neuritis (VN) has an association with peripheral vestibular lesions. The purpose of this study was to investigate whether the severity of vestibular dysfunction has an association with the presence of PD., Methods: We reviewed the medical records of 88 consecutive unilateral VN patients with unilateral canal paresis in caloric testing. Caloric test, cervical vestibular evoked myogenic potential test to air-conducted sound (ACS cVEMP), ocular vestibular evoked myogenic potential test to bone-conducted vibration (BCV oVEMP) and video head impulse test (vHIT) were used as vestibular function tests. Binomial logistic regression analyses were performed to see whether the subjects' age, sex, disease duration or the presence of PD is associated with the presence of vestibular dysfunction., Results: Seventeen (19%) experienced an episode of PD. There was no significant association between the presence of PD and abnormality in ACS cVEMPs, BCV oVEMPs, vHIT for the posterior semicircular canal (SCC) or vHIT for the lateral SCC. The presence of PD had a significant positive association with abnormality in vHIT for the anterior SCC (ASCC) (p = 0.0248)., Conclusions: The presence of PD in VN may be associated with the peripheral vestibular lesion., (© 2025 The Author(s). Clinical Otolaryngology published by John Wiley & Sons Ltd.)

How the fate (folding versus degradation) of glycoproteins is determined in the endoplasmic reticulum (ER) is an intriguing question. Monoglucosylated glycoproteins are recognized by lectin chaperones to facilitate their folding, whereas glycoproteins exposing well-trimmed mannoses are subjected to glycoprotein ER-associated degradation (gpERAD); we have elucidated how mannoses are sequentially trimmed by EDEM family members (George et al., 2020; 2021 eLife). Although reglucosylation by UGGT was previously reported to have no effect on substrate degradation, here we directly tested this notion using cells with genetically disrupted UGGT1/2. Strikingly, the results showed that UGGT1 delayed the degradation of misfolded substrates and unstable glycoproteins including ATF6α. An experiment with a point mutant of UGGT1 indicated that the glucosylation activity of UGGT1 was required for the inhibition of early glycoprotein degradation. These and overexpression-based competition experiments suggested that the fate of glycoproteins is determined by a tug-of-war between structure formation by UGGT1 and degradation by EDEMs. We further demonstrated the physiological importance of UGGT1, since ATF6α cannot function properly without UGGT1. Thus, our work strongly suggests that UGGT1 is a central factor in ER protein quality control via the regulation of both glycoprotein folding and degradation., Competing Interests: SN, MM, DY, SO, SA, KM, MT, AF, MY, KS, SS, KI, YK, TS, TY, HY, KK, KM No competing interests declared, (© 2023, Ninagawa, Matsuo, Ying et al.)

Heavy water, containing the heavy hydrogen isotope, is toxic to cells, although the underlying mechanism remains incompletely understood. In addition, certain enzymatic proton transfer reactions exhibit kinetic isotope effects attributed to hydrogen isotopes and their temperature dependencies, indicative of quantum tunneling phenomena. However, the correlation between the biological effects of heavy water and the kinetic isotope effects mediated by hydrogen isotopes remains elusive. In this study, we elucidated the kinetic isotope effects arising from hydrogen isotopes of water and their temperature dependencies in vitro, focusing on deacetylation, DNA cleavage, and protein cleavage, which are crucial enzymatic reactions mediated by hydrolysis. Intriguingly, the intracellular isotope effects of heavy water, related to the in vitro kinetic isotope effects, significantly impeded multiple DNA double-strand break repair mechanisms crucial for cell survival. Additionally, heavy water exposure enhanced histone acetylation and associated transcriptional activation in cells, consistent with the in vitro kinetic isotope effects observed in histone deacetylation reactions. Moreover, as observed for the in vitro kinetic isotope effects, the cytotoxic effect on cell proliferation induced by heavy water exhibited temperature-dependency. These findings reveal the substantial impact of heavy water-induced isotope effects on cellular functions governed by hydrolytic enzymatic reactions, potentially mediated by quantum-level mechanisms underlying kinetic isotope effects., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yasuda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

There are neither predictive tests nor preventive strategies/treatments for acute promyelocytic leukemia (APL)-associated bleeding/thrombosis incidence. We encountered the case of a woman in her 70s who was admitted due to sudden-onset right hemiparesis. The patient was diagnosed with acute cerebral infarction as the initial manifestation of APL. Intravenous recombinant human soluble thrombomodulin was initiated on admission, followed by oral all-trans retinoic acid two days later. However, the patient's condition deteriorated due to APL-associated diphasic cerebral infarction with left internal carotid artery occlusion, and she died 10 days after admission. Thus, the degree of main artery stenosis should be evaluated before treatment in patients with APL who have coagulopathy., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Ethical Review Board of Nihonkai General Hospital issued approval 006-1-6. The patient’s daughter provided written informed consent for the publication of this report after the patient’s death. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Suzuki et al.)

Bing-Neel syndrome, a rare neurological complication of Waldenström macroglobulinemia, is caused by the direct infiltration of malignant lymphoplasmacytic cells into the central nervous system. We report a patient who presented with back pain, weakness, lower extremity numbness, and gait disturbance accompanied by immunoglobulin M paraproteinemia and lymphoplasmacytic lymphoma in the bone marrow. Thoracic and lumbar magnetic resonance imaging revealed a long paravertebral mass around the spinal column, but the direct infiltration could not be proven. The patient was diagnosed with possible Bing-Neel syndrome and managed with bendamustine and rituximab. After chemotherapy, the patient's neurological and radiological findings improved. Magnetic resonance imaging should be considered when the Bing-Neel syndrome diagnosis is unclear., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

It remains uncertain how global genome nucleotide excision repair (GG-NER) efficiently removes various helix distorting DNA lesions in the cell nucleus. Here, we present a protocol to assess the contribution of factors of interest to GG-NER using two types of fluorescence-microscopy-based techniques. First, we describe steps for analyzing the localization of the factors upon local ultraviolet (UV) irradiation. We then detail the second technique, which quantifies the removal of UV-induced photolesions combined with lesion-specific antibodies and program-based image analysis. For complete details on the use and execution of this protocol, please refer to Kusakabe et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Acrylamide, a common food contaminant, is metabolically activated to glycidamide, which reacts with DNA at the N7 position of dG, forming N7-(2-carbamoyl-2-hydroxyethyl)-dG (GA 7 dG). Owing to its chemical lability, the mutagenic potency of GA 7 dG has not yet been clarified. We found that GA 7 dG undergoes ring-opening hydrolysis to form N 6 -(2-deoxy-d-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-[N-(2-carbamoyl-2-hydroxyethyl)formamido]pyrimidine (GA-FAPy-dG), even at neutral pH. Therefore, we aimed to examine the effects of GA-FAPy-dG on the efficiency and fidelity of DNA replication using an oligonucleotide carrying GA-FAPy-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)guanine (dfG), a 2'-fluorine substituted analog of GA-FAPy-dG. GA-FAPy-dfG inhibited primer extension by both human replicative DNA polymerase ε and the translesion DNA synthesis polymerases (Polη, Polι, Polκ, and Polζ) and reduced the replication efficiency by less than half in human cells, with single base substitution at the site of GA-FAPy-dfG. Unlike other formamidopyrimidine derivatives, the most abundant mutation was G:C > A:T transition, which was decreased in Polκ- or REV1-KO cells. Molecular modeling suggested that a 2-carbamoyl-2-hydroxyethyl group at the N 5 position of GA-FAPy-dfG can form an additional H-bond with thymidine, thereby contributing to the mutation. Collectively, our results provide further insight into the mechanisms underlying the mutagenic effects of acrylamide., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the effects of self-management vestibular rehabilitation (VR) on the subjective symptoms of dizziness and postural stability in persistent postural-perceptual dizziness (PPPD)., Study Design: Retrospective case review., Methods: The medical records of 30 patients newly diagnosed with PPPD based on the Bárány Society's diagnostic criteria were reviewed. Nineteen patients (4 males and 15 females; age range 27-84 years, mean age ± standard deviation 57.4 ± 14.2 years) who was newly instructed to self-management VR were included and instructed to perform self-management VR for 2 months., Results: One patient did not visit the outpatient clinic again, and in the remaining 18 patients, 4 (22%) discontinued VR at their own discretion. In the 12 patients who completed 2 months of VR (67%), there was a significant improvement in Niigata PPPD Questionnaire (NPQ) and Dizziness Handicap Inventory (DHI) scores after VR compared to those before VR ( p  < .05). However, the mean velocity of center of pressure (COP) movement (velocity) and the envelopment area traced by COP movement (area), as well as the Romberg ratio and foam ratio of velocity and area, did not differ significantly after VR when compared to those before VR ( p  > .05)., Conclusions: For PPPD, self-management VR improved subjective symptoms of dizziness, but not stability of standing posture. It is necessary to improve patients' adherence to the treatment., Level of Evidence: 4., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This work received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors., (© 2023 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Nucleotide excision repair removes DNA lesions caused by ultraviolet light, cisplatin-like compounds and bulky adducts 1 . After initial recognition by XPC in global genome repair or a stalled RNA polymerase in transcription-coupled repair, damaged DNA is transferred to the seven-subunit TFIIH core complex (Core7) for verification and dual incisions by the XPF and XPG nucleases 2 . Structures capturing lesion recognition by the yeast XPC homologue Rad4 and TFIIH in transcription initiation or DNA repair have been separately reported 3-7 . How two different lesion recognition pathways converge and how the XPB and XPD helicases of Core7 move the DNA lesion for verification are unclear. Here we report on structures revealing DNA lesion recognition by human XPC and DNA lesion hand-off from XPC to Core7 and XPA. XPA, which binds between XPB and XPD, kinks the DNA duplex and shifts XPC and the DNA lesion by nearly a helical turn relative to Core7. The DNA lesion is thus positioned outside of Core7, as would occur with RNA polymerase. XPB and XPD, which track the lesion-containing strand but translocate DNA in opposite directions, push and pull the lesion-containing strand into XPD for verification., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Impairment of visual fixation suppression (VS) in progressive supranuclear palsy (PSP) is not well documented., Objective: To evaluate the usefulness of impaired VS of caloric nystagmus as an index for differential diagnosis between PSP and Parkinson's disease (PD), which is often difficult, especially in the early stage., Methods: Subjects comprised 26 PSP patients and 26 PD patients clinically diagnosed at Tokyo Metropolitan Neurological Hospital. We retrospectively investigated VS of caloric nystagmus, horizontal pursuit, saccades, and horizontal optokinetic nystagmus recorded on direct-current-electronystagmography, and neuroradiological findings., Results: The median of the average VS% was 0% and 50.0% in PSP and PD patients, respectively. In PSP, VS was impaired even in the early stage of disease. We found a significant correlation between VS and velocity of saccades or maximum slow phase velocity of optokinetic nystagmus only in PSP patients. PSP patients with atrophy of the subthalamic nucleus or with decreased blood flow in the frontal lobe showed significantly more severe impairment of VS., Conclusions: VS may be a useful biomarker to differentiate patients with PSP from those with PD. Cerebellar networks that connect with the cerebral cortex and basal ganglia may contribute to impaired VS of caloric nystagmus in PSP.

The XPC protein complex plays a central role in DNA lesion recognition for global genome nucleotide excision repair (GG-NER). Lesion recognition can be accomplished in either a UV-DDB-dependent or -independent manner; however, it is unclear how these sub-pathways are regulated in chromatin. Here, we show that histone deacetylases 1 and 2 facilitate UV-DDB-independent recruitment of XPC to DNA damage by inducing histone deacetylation. XPC localizes to hypoacetylated chromatin domains in a DNA damage-independent manner, mediated by its structurally disordered middle (M) region. The M region interacts directly with the N-terminal tail of histone H3, an interaction compromised by H3 acetylation. Although the M region is dispensable for in vitro NER, it promotes DNA damage removal by GG-NER in vivo , particularly in the absence of UV-DDB. We propose that histone deacetylation around DNA damage facilitates the recruitment of XPC through the M region, contributing to efficient lesion recognition and initiation of GG-NER., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Objectives: It remains unclear whether the dominance of 1000 Hz responses over responses at 500 Hz in cervical vestibular evoked myogenic potentials (cVEMPs) are characteristic of endolymphatic hydrops (EH), due to the presence of patients with absent responses at both frequencies. The purpose of the present study is to examine whether the dominant cVEMP responses at 1000 Hz over 500 Hz are characteristic findings of EH-related diseases among patients who show various cVEMP findings., Design: We retrospectively reviewed the medical records of 470 consecutive patients who underwent cVEMP testing with short-tone bursts at both 500 Hz and 1000 Hz. We categorized the cVEMP responses of these 470 patients into the following five groups: (group 1) present responses at both frequencies bilaterally, (group 2) present responses at 500 Hz but absent at 1000 Hz on at least one side, (group 3) absent responses at 500 Hz but present at 1000 Hz on at least one side, (group 4) absent responses at both frequencies on one side and present at both frequencies on the other side, and (group 5) absent responses at both frequencies bilaterally. We compared the proportion of EH-related diseases between each group and the other four groups and then investigated any increased or decreased disease incidence in each group., Results: In group 3, the proportion of EH-related disease was significantly higher (p < 0.01), and the incidence of an EH-related disease was greatly increased (standard residual value > 3)., Conclusions: cVEMPs that are absent at 500 Hz and present at 1000 Hz may be characteristic of EH-related disease., Competing Interests: C.F. is receiving a grant (18K09369) from Japan Society for the Promotion of Science (JSPS) for this work. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

SIRT2 and SIRT3 protein deacetylases maintain genome integrity and stability. However, their mechanisms for maintaining the genome remain unclear. To examine the roles of SIRT2 and SIRT3 in DSB repair, I-SceI-based GFP reporter assays for HR, single-strand annealing (SSA) and nonhomologous end joining (NHEJ) repair were performed under SIRT2- or SIRT3-depleted conditions. SIRT2 or SIRT3 depletion inhibited HR repair equally to RAD52 depletion, but did not affect SSA and NHEJ repairs. SIRT2 or SIRT3 depletion disturbed the recruitment of RAD51 to DSB sites, an essential step for RAD51-dependent HR repair, but not directly through RAD52 deacetylation. SIRT2 or SIRT3 depletion decreased the colocalization of γH2AX foci with RPA1, and thus, they might be involved in initiating DSB end resection for the recruitment of RAD51 to DSB sites at an early step in HR repair. These results show the novel underlying mechanism of the SIRT2 and SIRT3 functions in HR for genome stability., (© 2021 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Nucleotide excision repair (NER) is a pathway involved in the repair of a variety of potentially mutagenic lesions that distort the DNA double helix. The ubiquitin E3-ligase complex UV-DDB is required for the recognition and repair of UV-induced cyclobutane pyrimidine dimers (CPDs) lesions through NER. DDB2 directly binds CPDs and subsequently undergoes ubiquitination and proteasomal degradation. DDB2 must remain on damaged chromatin, however, for sufficient time to recruit and hand-off lesions to XPC, a factor essential in the assembly of downstream repair components. Here we show that the tumor suppressor USP44 directly deubiquitinates DDB2 to prevent its premature degradation and is selectively required for CPD repair. Cells lacking USP44 have impaired DDB2 accumulation on DNA lesions with subsequent defects in XPC retention. The physiological importance of this mechanism is evident in that mice lacking Usp44 are prone to tumors induced by NER lesions introduced by DMBA or UV light. These data reveal the requirement for highly regulated ubiquitin addition and removal in the recognition and repair of helix-distorting DNA damage and identify another mechanism by which USP44 protects genomic integrity and prevents tumors., Competing Interests: PG owns stock in Abbott laboratories, Abbvie, and Johnson and Johnson. OF is employed by the company Genentech. These companies had no influence on the design or interpretation of the study—nor the writing of the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Mandemaker, Matsumoto, Foreman, Holland, Lloyd, Sugasawa, Vermeulen, Marteijn and Galardy.)

Objective: To determine minimally important differences (MIDs) for subjective improvement in postural stability after a therapeutic intervention in patients with bilateral vestibulopathy (BVP)., Methods: Thirteen BVP patients received noisy galvanic vestibular stimulation (nGVS) for 30 min and their static posture with eyes closed was monitored after the stimuli. The velocity of the center of pressure (COP) movement, the area enclosed by the COP movement, and the root mean square (RMS) of the displacement of the COP were measured for 30 s. Subjective evaluation of postural stability after nGVS was graded as worsened, slightly worsened, unchanged, slightly improved and improved in comparison with postural stability measured without nGVS. Anchor-based methods were used to estimate MIDs for subjective improvement. Velocity, area and RMS for each anchor-response group were averaged (2 sessions, each with 5 measurement periods during 3 h after the stimuli). The mean changes between the slightly improved group and unchanged group were used as estimates for MID for improvement., Results: A total of 129 anchors were analyzed. Subjective evaluations numbered 83 (64%) for unchanged and 33 (26%) for slightly improved. Anchor-based methods yielded estimates for MIDs of -0.43 cm/s in velocity improvement (p < 0.01), -0.77 cm 2 for area improvement (p < 0.01) and -0.23 cm for RMS improvement (p < 0.001)., Conclusion: The present study provides the estimation of MIDs for improving postural stability in BVP patients and may be useful for interpreting whether the results from clinical trials are meaningful in future studies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Squamous cell carcinoma (SCC) occurs frequently in the human Xeroderma Pigmentosum (XP) syndrome and is characterized by deficient UV-damage repair. SCC is the most common equine ocular cancer and the only associated genetic risk factor is a UV-damage repair protein. Specifically, a missense mutation in horse DDB2 (T338M) was strongly associated with both limbal SCC and third eyelid SCC in three breeds of horses (Halflinger, Belgian, and Rocky Mountain Horses) and was hypothesized to impair binding to UV-damaged DNA. Here, we investigate DDB2-T338M mutant's capacity to recognize UV lesions in vitro and in vivo, together with human XP mutants DDB2-R273H and -K244E. We show that the recombinant DDB2-T338M assembles with DDB1, but fails to show any detectable binding to DNA substrates with or without UV lesions, due to a potential structural disruption of the rigid DNA recognition β-loop. Consistently, we demonstrate that the cellular DDB2-T338M is defective in its recruitment to focally radiated DNA damages, and in its access to chromatin. Thus, we provide direct functional evidence indicating the DDB2-T338M recapitulates molecular defects of human XP mutants, and is the causal loss-of-function allele that gives rise to equine ocular SCCs. Our findings shed new light on the mechanism of DNA recognition by UV-DDB and on the initiation of ocular malignancy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ribonucleoside triphosphates are often incorporated into genomic DNA during DNA replication. The accumulation of unrepaired ribonucleotides is associated with genomic instability, which is mediated by DNA topoisomerase 1 (Top1) processing of embedded ribonucleotides. The cleavage initiated by Top1 at the site of a ribonucleotide leads to the formation of a Top1-DNA cleavage complex (Top1cc), occasionally resulting in a DNA double-strand break (DSB). In humans, tyrosyl-DNA phosphodiesterases (TDPs) are essential repair enzymes that resolve the trapped Top1cc followed by downstream repair factors. However, there is limited cellular evidence of the involvement of TDPs in the processing of incorporated ribonucleotides in mammals. We assessed the role of TDPs in mutagenesis induced by a single ribonucleotide embedded into DNA. A supF shuttle vector site-specifically containing a single riboguanosine (rG) was introduced into the human lymphoblastoid TK6 cell line and its TDP1-, TDP2-, and TDP1/TDP2-deficient derivatives. TDP1 and TDP2 insufficiency remarkably decreased the mutant frequency caused by an embedded rG. The ratio of large deletion mutations induced by rG was also substantially lower in TDP1/TDP2-deficient cells than wild-type cells. Furthermore, the disruption of TDPs reduced the length of rG-mediated large deletion mutations. The recovery ratio of the propagated plasmid was also increased in TDP1/TDP2-deficient cells after the transfection of the shuttle vector containing rG. The results suggest that TDPs-mediated ribonucleotide processing cascade leads to unfavorable consequences, whereas in the absence of these repair factors, a more error-free processing pathway might function to suppress the ribonucleotide-induced mutagenesis. Furthermore, base substitution mutations at sites outside the position of rG were detected in the supF gene via a TDPs-independent mechanism. Overall, we provide new insights into the mechanism of mutagenesis induced by an embedded ribonucleotide in mammalian cells, which may lead to the fatal phenotype in the ribonucleotide excision repair deficiency., Competing Interests: The authors have declared that no competing interests exist.

The ubiquitin-proteasome system (UPS) plays crucial roles in regulation of various biological processes, including DNA repair. In mammalian global genome nucleotide excision repair (GG-NER), activation of the DDB2-associated ubiquitin ligase upon UV-induced DNA damage is necessary for efficient recognition of lesions. To date, however, the precise roles of UPS in GG-NER remain incompletely understood. Here, we show that the proteasome subunit PSMD14 and the UPS shuttle factor RAD23B can be recruited to sites with UV-induced photolesions even in the absence of XPC, suggesting that proteolysis occurs at DNA damage sites. Unexpectedly, sustained inhibition of proteasome activity results in aggregation of PSMD14 (presumably with other proteasome components) at the periphery of nucleoli, by which DDB2 is immobilized and sequestered from its lesion recognition functions. Although depletion of PSMD14 alleviates such DDB2 immobilization induced by proteasome inhibitors, recruitment of DDB2 to DNA damage sites is then severely compromised in the absence of PSMD14. Because all of these proteasome dysfunctions selectively impair removal of cyclobutane pyrimidine dimers, but not (6-4) photoproducts, our results indicate that the functional integrity of the proteasome is essential for the DDB2-mediated lesion recognition sub-pathway, but not for GG-NER initiated through direct lesion recognition by XPC.

We report a case of acute vestibulopathy with the simultaneous involvement of both superior and inferior vestibular nerves on both sides. A 36-year-old female presented with dizziness, oscillopsia and a walking impairment subsequent to a high fever. Vestibular function tests including caloric testing, video head impulse testing (vHIT) and cervical and ocular vestibular evoked myogenic potentials (cVEMPs and oVEMPs) were performed. In the first examination, vHIT and caloric testing showed severe impairments in all three semicircular canals in each ear, and both cVEMPs and oVEMPs were absent on both sides. During a 1-year follow-up, the gain of vHIT gradually recovered by more than 0.5 to normal. cVEMPs also recovered to normal on both sides while oVEMPs remained absent on both sides. This is the first reported case of acute bilateral vestibulopathy with simultaneous involvement of both superior and inferior vestibular nerves on both sides. Repeated evaluation of vestibular function using vHIT, cVEMPs and oVEMPs is helpful to assess the time course of recovery in patients with vestibulopathy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Although tyrosine kinase inhibitors markedly improve the clinical outcome of chronic myeloid leukemia (CML), blast crisis in CML (CML-BC) still has a poor prognosis. Many chromosomal abnormalities have been reported in CML-BC and may contribute to therapeutic resistance, disease progression, and prognosis. Herein, we report a rare chromosome abnormality with der(16)t(1;16)(q12;q11.2) in CML-BC. It has been demonstrated that this chromosomal abnormality is associated with disease progression and poor prognosis in other malignancies, such as Ewing sarcoma. A 70-year-old man with CML who had been treated with imatinib and dasatinib was admitted to our hospital after complaining for several weeks of fatigue and dyspnea and diagnosed with CML-BC. His tumor cells presented additional chromosomal abnormality with der(16)t(1;16)(q12;q11.2), which has never been reported in CML cases. We successfully treated him using cytotoxic agents combined with ponatinib, and this chromosome abnormality was detected via G-banding. Our patient has lived for over 8 months without any progression with ponatinib treatment alone. Although the biological function of this chromosomal abnormality remains unclear, the satellite DNA of 1q12, which induces genomic instability in other malignancies, and the loss of 16q may contribute to the disease progression of CML in this case. In conclusion, this paper is the first to report on the case of CML-BC with der(16)t(1;16)(q12;q11.2)., Competing Interests: The authors have no conflicts of interest to declare related to this case report., (Copyright © 2020 by S. Karger AG, Basel.)