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This article, published in the European Journal of Immunology, explores the role of interleukin 21 (IL-21) in the differentiation of plasma cells and the inhibition of IgE expression. The study found that IL-21 promotes the differentiation of IgG1+ plasma cells instead of class switching to IgE by inducing the expression of Blimp1. The researchers demonstrated this through experiments using B cells and mice, showing that IL-21 inhibits the generation of IgE+ cells and promotes the differentiation of IgG1+ plasma cells. These findings suggest that IL-21 plays a role in regulating the production of IgE and may have implications for understanding allergic reactions and asthma. [Extracted from the article]

Objective: In benign paroxysmal positional vertigo (BPPV), positional nystagmus becomes generally weaker when the Dix–Hallpike test is repeated. This phenomenon is termed BPPV fatigue. We previously reported that the effect of BPPV fatigue deteriorates over time (i.e., the positional nystagmus is observed again after maintaining a sitting head position). The aim of this study was to investigate whether the effect of BPPV fatigue attenuates after maintaining a supine position with the head turned to the affected side. Methods: Twenty patients with posterior-canal-type BPPV were assigned to two groups. Group A received Dix–Hallpike test, were returned to the sitting position (reverse Dix–Hallpike test) with a sitting head position for 10 min, and then received a second Dix–Hallpike test. Group B received Dix–Hallpike test, were kept in the supine position with the head turned to the affected side for 10 min, and then received reverse Dix–Hallpike test followed by the second Dix–Hallpike test. The maximum slow phase eye velocity (MSPEV) of positional nystagmus induced by the first, reverse, and second Dix–Hallpike test were analyzed. Results: The ratio of MSPEV of the positional nystagmus induced by the second Dix–Hallpike test relative to the first Dix–Hallpike test was significantly smaller in group B than that in group A. There was no difference in the MSPEV of the positional nystagmus induced by the reverse Dix–Hallpike test between group A and B. Conclusions: The effect of BPPV fatigue is continued by maintaining a supine position with the head turned to the affected side, while the effect is weakened by maintaining a sitting head position. On the basis of the most widely accepted theory of the pathophysiology of BPPV fatigue, in which the particles become dispersed along the canal during head movement in the Dix–Hallpike test, we found an inconsistency whereby the dispersed otoconial debris return to a mass during the sitting position but do not return to a mass in the supine position with the head turned to the affected side. Future studies are required to determine the exact pathophysiology of BPPV fatigue. Classification of Evidence: 2b. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate whether the insertion of an implant into the cochlea is accompanied by a deterioration in otolith function. Cervical and ocular vestibular evoked myogenic potentials (cVEMP and oVEMP) and linear vestibulo-ocular reflex (lVOR) during eccentric rotation were assessed before and after cochlear implantation (CI) to evaluate otolith function.Methods: Twelve patients with bilateral severe sensorineural hearing loss who had undergone CI surgery in our hospital between May 2016 and November 2017 were included in this study. cVEMP and oVEMP were assessed using the asymmetry ratio (AR), calculated with the following formula: [(peak-to-peak amplitude calculated as the sum of the p13 and n23 amplitudes in the non-operated side) - (that in the operated side)]/[(that in the non-operated side) + (that in the operated side)]. The ratio of VOR gain during eccentric rotation against VOR gain during center rotation was used to assess lVOR. For eccentric rotation, patients were rotated while displaced from the axis of rotation. At the same time, linear acceleration stimulated the utricle and induced lVOR. All patients underwent cVEMP and oVEMP tests and center and eccentric rotation tests before and about 30days after CI surgery.Results: Three patients with absent cVEMP responses before surgery were excluded, leaving pre-surgery cVEMP results for 9/12 patients. In five of these patients, the AR of cVEMP increased after CI, indicating that saccular function, as evaluated by cVEMP, did not deteriorate significantly postoperatively. One patient with an absent oVEMP response before CI was excluded, leaving pre-surgery oVEMP results for 11/12 patients. In 10 of these patients, the AR of oVEMP increased after CI surgery, indicating that utricular function, as evaluated by oVEMP, deteriorated significantly postoperatively. However, because the ratio of VOR gain during eccentric rotation against VOR gain during center rotation did not become worse after CI, utricular function, as evaluated by lVOR, did not deteriorate significantly postoperatively. Symptoms of vertigo became worse after CI in two of the 12 patients.Conclusion: CI does not cause a deterioration in saccular function, as evaluated by cVEMP. Although CI does cause a deterioration in utricular function in oVEMP tests, this is not consistent in lVOR tests. These results indicate that CI causes a slight deterioration in utricular function that is insufficient to cause vertigo or deterioration of lVOR. [ABSTRACT FROM AUTHOR]

The aim of this study was to propose a new pathophysiological hypothesis for involuntary eye oscillation in infantile nystagmus (IN): patients with IN exhibit impaired gaze fixation, horizontal smooth pursuit and optokinetic nystagmus (OKN) and use saccadic eye movements for these underlying impairments. In order to induce saccades, they make enough angle between gaze and target by precedent exponential slow eye movements. IN consists of the alternate appearance of the saccade and the slow eye movements. Unlike most previous theories, IN is therefore considered a necessary strategy allowing for better vision and not an obstacle to clear vision. In five patients with IN, eye movements were analyzed during the smooth pursuit test, saccadic eye movement test, OKN test and vestibulo-ocular reflex (VOR) test. Their gaze fixation, horizontal smooth pursuit, OKN and the last half of the slow phase of VOR were impaired. The lines obtained by connection of the end eye positions of fast phase of nystagmus coincided with the trajectories of targets. The findings indicate that patients followed the target by the fast but not the slow phase of nystagmus, which supports our hypothesis. By setting the direction of slow phase of nystagmus opposite to the direction of the OKN stimulation, enough angle can be effectively made between the gaze and target for the induction of saccade. This is the mechanism of reversed OKN response. In darkness and when eyes are closed, IN weakens because there is no visual target and neither the saccade for catching up the target or slow phase for induction of the saccade is needed. [ABSTRACT FROM AUTHOR]

Conclusion: Contrast-enhanced magnetic resonance imaging (MRI) reveals variations in the endolymphatic morphology of the cystic lateral semicircular canal (CLSC) that correlate with inner ear function. This report is the first to suggest a relationship between the morphology and function of this common inner ear malformation in clinical cases. Objectives: This study investigated the radiological and functional findings of a common inner ear malformation using computed tomography (CT), gadolinium contrast-enhanced magnetic resonance imaging (MRI), caloric testing, and cervical and ocular vestibular evoked myogenic potential (VEMP) testing. Method: Four ears in three patients who were radiologically diagnosed with a CLSC and a normal cochlea on high-resolution CT and contrast-enhanced MRI were included. Semicircular canal and vestibular functions were analyzed using the caloric test and cervical and ocular VEMP testing. Results: Unilateral and bilateral cystic canals were found in two and one patients, respectively. In the first patient, the malformed vestibule and cystic space were separate on imaging, and perilymph filled the cystic space. The functional test results were normal. In the second patient, endolymph filled both cystic spaces, and the functional responses were poor. In the third patient, endolymph filled the cystic space, and the ear did not respond during functional testing. [ABSTRACT FROM AUTHOR]

Conclusions: Postural control is dependent on the visual system in normal conditions. Shift from visual to somatosensory dependence in dizzy patients suggests that utilizing the stable visual references is recommended for the rehabilitation of dizzy patients. Objectives: To investigate which of the visual or somatosensory system is mainly used for substitution of the impaired spatial orientation in dizzy patients. Methods: We recruited 189 consecutive patients with or without dizziness and vestibular dysfunction. Dizzy patients were divided into three groups: acute, episodic, and chronic dizziness. Vestibular function was assessed by caloric test, traditional head impulse test, and head shaking nystagmus. Visual or somatosensory dependence of spatial orientation was assessed by posturography on a solid surface or on foam in eyes open or closed condition. The foam ratio (posturography with/without foam) when eyes were closed was indicative of somatosensory dependence of postural control, whereas the Romberg ratio on foam showed visual dependence. (Romberg ratio on foam)/(foam ratio with eyes closed) was calculated and used as an index of the visual/somatosensory dependence of postural control. Results: The visual/somatosensory ratio of postural control was significantly lower in dizzy patients as well as patients with vestibular dysfunction, however, no differences were found between acute, episodic, and chronic dizziness. [ABSTRACT FROM AUTHOR]

In examining 181 patients (327 ears) with sensorineural hearing loss of unknown etiology and 25 people (50 ears) with normal hearing by high-resolution computed tomography (CT), the image of the large vestibular aqueduct (VA) was defined as being a visible large aperture (≥4 mm), and small distance between vestibule and traceable part of the VA nearest to the vestibule (≥1 mm). The large VA was found in 13 patients (23 ears, 7.0%); it was relatively frequent following hypoplastic cochlea (33 ears, 10.1%) in all the inner ear anomalies detected. In patients with large VA, high-frequency hearing was affected more than low frequency, and history of sudden hearing loss was observed frequently (61% of ears with large VA), which was found to be triggered by characteristic episodes such as minor head trauma, etc. Those clinical features were observed more in those without cochlear anomaly than in those accompanying cochlear anomaly. Pathogenesis of sensorineural hearing loss and characteristic fluctuation of hearing in those patients are discussed. [ABSTRACT FROM AUTHOR]

Thalidomide was sold worldwide as a sedative over 60 years ago, but it was quickly withdrawn from the market due to its teratogenic effects. Thalidomide was later found to have therapeutic effects in several diseases, although the molecular mechanisms remained unclear. The discovery of cereblon (CRBN), the direct target of thalidomide, a decade ago greatly improved our understanding of its mechanism of action. Accumulating evidence has shown that CRBN functions as a substrate of Cullin RING E3 ligase (CRL4CRBN), whose specificity is controlled by ligands such as thalidomide. For example, lenalidomide and pomalidomide, well-known thalidomide derivatives, degrade the neosubstrates Ikaros and Aiolos, resulting in anti-proliferative effects in multiple myeloma. Recently, novel CRBN-binding drugs have been developed. However, for the safe handling of thalidomide and its derivatives, a greater understanding of the mechanisms of its adverse effects is required. The teratogenic effects of thalidomide occur in multiple tissues in the developing fetus and vary in phenotype, making it difficult to clarify this issue. Recently, several CRBN neosubstrates (e.g., SALL4 (Spalt Like Transcription Factor 4) and p63 (Tumor Protein P63)) have been identified as candidate mediators of thalidomide teratogenicity. In this review, we describe the current understanding of molecular mechanisms of thalidomide, particularly in the context of its teratogenicity. [ABSTRACT FROM AUTHOR]

• Participants were rotated with displacement from the axis of rotation. • Eye movements were analyzed three-dimensionally. • Recognition of the direction of centripetal acceleration was analyzed. This study was conducted to evaluate the linear vestibulo-ocular reflex (lVOR) mediated by the saccule, and to investigate the relationship between the lVOR and the ability to distinguish the direction of centripetal acceleration during centric and eccentric rotation. Participants sat on a chair in darkness, with the right ear facing downwards, either directly above the center of rotation, or with their nose out, nose in, right shoulder out, or left shoulder out against the center of rotation (eccentric rotation). Participants were given no information about the chair position, and were rotated sinusoidally at 0.1–0.7 Hz. Three-dimensional eye movements during rotation were analyzed. Participants were asked to describe the position of the chair after rotation. Correctly reporting the five possible chair positions requires recognition of the direction of centripetal acceleration. We analyzed the rate of correct answers to assess participants' ability to identify the direction of centripetal acceleration. lVOR mediated by the saccule was observed only at high rotational frequencies. The rate of correct answers was higher at high rotational frequencies than that at low rotational frequencies. These results indicate that high rotational frequency is important for both lVOR mediated by the saccule and distinguishing the direction of centripetal acceleration. [ABSTRACT FROM AUTHOR]

Objective: This study was performed to determine whether endolymphatic sac surgery improves vestibular and cochlear endolymphatic hydrops 2 years after sac surgery and to elucidate the relationship between the degree of improvement of endolymphatic hydrops and the changes in vertigo symptoms, the hearing level, and the summating potential/action potential ratio (-SP/AP ratio) by electrocochleography (ECochG) in patients with Ménière's disease (MD).Methods: Twenty-one patients with unilateral MD who underwent sac surgery were included in this study. All patients underwent gadolinium-enhanced magnetic resonance imaging (Gd-MRI) before and 2 years after sac surgery. We evaluated the difference in vestibular and cochlear endolymphatic hydrops between before and after surgery in both ears and compared these findings with the frequency of vertigo attacks, hearing level, and ECochG findings.Results: In affected ears, the presence of vestibular endolymphatic hydrops and the frequency of vertigo attacks significantly decreased after surgery. However, affected ears showed no significant improvement in the presence of cochlear endolymphatic hydrops or the -SP/AP ratio by ECochG; there was also no significant improvement or deterioration in the hearing level.Conclusion: The present findings suggest that sac surgery reduces vestibular endolymphatic hydrops and prevents aggravation of cochlear endolymphatic hydrops, and these changes lead to a reduction of vertigo attacks and suppress the progression of hearing impairment associated with vertigo attacks. [ABSTRACT FROM AUTHOR]

A dialkylbis(germanolato)zirconium complex was synthesized by taking advantage of a novel bowl-shaped germanol as the ligand source, presenting the first example of a zirconium complex containing germanolato ligands. The bis(germanolato) complex as well as the analogous bis(silanolato) complex was found to exhibit catalytic activity for ethylene polymerization. [ABSTRACT FROM AUTHOR]

When a participant is rotated while displaced from the axis of rotation (eccentric rotation, ER), both rotational stimulation and linear acceleration are applied to the participant. As linear acceleration stimulates the otolith, the vestibulo-ocular reflex (VOR) caused by the otolith (linear VOR; lVOR) would be induced during ER. Ten participants were rotated sinusoidally at a maximum angular velocity of 50°/s and at frequencies of 0.1, 0.3, 0.5, and 0.7 Hz. The radius of rotation during ER was 90 cm. The participants sat on a chair at three different positions: on the axis (center rotation, CR), at 90 cm backward from the axis (nose-in ER, NI-ER) and at 90 cm forward from the axis (nose-out ER, NO-ER). Their eye movements during rotation were recorded and analyzed three-dimensionally. The VOR gain during NI-ER was lower at 0.5 and 0.7 Hz, and that during NO-ER was higher at 0.3, 0.5, and 0.7 Hz than during CR. These results indicate that lVOR actually worked at 0.5 and 0.7 Hz during ER and that the enhancement and decline of the VOR gain relative to the VOR gain during CR was seen in humans. Thus, we suggest that otolith function can be assessed via rotational testing of NI-ER and NO-ER. [ABSTRACT FROM AUTHOR]

Objective: Posturography (PG) shows various patterns corresponding to a patient's equilibrium condition; however, PG is not useful for the differential diagnosis of peripheral vestibular diseases (PVDs). The aim of this study was to identify parameters of PG that can distinguish between PVDs.Methods: The differences in PG parameters between PVDs were evaluated retrospectively. Two hundred and two patients with Ménière's disease (MD), 154 patients with benign paroxysmal positional vertigo (BPPV), 20 patients with sudden sensorineural hearing loss with vertigo (SSNHLwV), and 31 patients with vestibular neuritis (VN) underwent PG during the non-acute phase of vertigo, from January 2010 to March 2017.Results: The velocity of body oscillation of BPPV patients with eyes open and closed were significantly faster than those of MD patients with eyes open (p < 0.001) and closed (p = 0.033). The velocity of body oscillation of VN patients with eyes open was significantly faster than that of MD patients with eyes open (p = 0.0083). There were no significant differences among the other PG parameters between PVDs. Although there were significant differences among the velocity with eyes open and closed between males and females (eye open: p = 0.0009, eye close: p < 0.0001), there was no significant difference in the ratio of males to females among PVDs (p = 0.1834). Therefore, the ratio did not influence the difference in velocity among PVDs. Patient age correlated with the velocity with eyes open (p < 0.001) and with eyes closed (p < 0.001). Post-hoc analysis revealed significant differences in patient age, and comparisons of MD and BPPV, MD and SSNHLwV, BPPV and VN, and VN and SSNHLwV. Therefore, we performed multiple regression analysis to determine whether the significant differences in the velocity of body oscillation among PVDs were caused by the difference in age distribution between PVD groups, rather than by differences in the PVDs themselves. There were correlations between age and the velocity of body oscillation with eyes open (p < 0.001) and with eyes closed (p < 0.001). There also were correlations between MD or VN and the velocity of body oscillation with eyes open (p = 0.0194).Conclusion: There were significant differences in the velocity of body oscillation with eyes open between MD and VN patients. The difference between MD and VN was significant regardless of the age distribution. To distinguish between MD and VN, the velocity of body oscillation with eyes open is a useful PG index. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effectiveness of unilateral posterior semicircular canal (PSCC)-plugging surgery for patients with intractable bilateral PSCC-type benign paroxysmal positional vertigo (P-BPPV).Methods: From July 2011 to December 2015, we diagnosed 136 patients with P-BPPV. Of these, 3 patients had bilateral P-BPPV, and in 2 of the 3, the condition had been refractory to conservative treatment for more than 1 year. We planned a staged PSCC-plugging surgery for these 2 patients; initially one side was treated, and the contralateral side was treated 6 months later.Results: After the first surgery, both patients experienced improvement in symptoms of vertigo and nystagmus on the operated side and no change on the non-operated side. Patients underwent the Epley maneuver for the non-operated side. In one case, the non-operated side was cured. In the other case, although the P-BPPV was not completely resolved, the patient was satisfied with the result of unilateral surgery because he was now able to turn in bed to the operated side without vertigo. Before surgery, he had experienced vertigo when turning even slightly in bed.Conclusion: We propose that even unilateral PSCC-plugging surgery is effective for some patients with intractable bilateral P-BPPV. [ABSTRACT FROM AUTHOR]

IgE is induced by the presence of IL-4 by class switching from IgM through IgG1 to IgE. IL-21 inhibits the IgE class switch by induction of Blimp1 leading to Stat6 and AID downregulation, and plasmablast/plasma cell differentiation., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Background: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs). Liquid biomarkers to predict irAE occurrence are urgently needed. We previously developed an ELISA system to specifically detect soluble PD-L1 (sPD-L1) with PD-1-binding capacity (bsPD-L1). Here, we investigated the relationship between sPD-L1 and bsPD-L1 in gastric cancer (GC) and non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 blockade and their association with irAEs. Methods: We examined sPD-L1, bsPD-L1, matrix metalloproteinases (MMPs), and proinflammatory cytokine levels by ELISA in plasma samples from 117 GC patients prior to surgery and 72 NSCLC patients prior to and at 2 months after ICI treatment (anti-PD-1, n = 48; anti-PD-L1, n = 24). In mice treated with anti-PD-1/PD-L1 antibodies (Abs), sPD-L1 levels and localization of Abs were examined by ELISA and immunohistochemistry, respectively. Results: sPD-L1 was detected with higher frequency in GC patients than in NSCLC patients, whereas bsPD-L1 was detected with similar frequencies in GC and NSCLC patients. sPD-L1 levels were correlated with IL-1α, IL-1β, TNF-α, and IL-6 levels, while bsPD-L1 levels were correlated with MMP13, MMP3, and IFN-γ levels. In NSCLC patients, anti-PD-L1, but not anti-PD-1, treatment increased sPD-L1, which was associated with irAE development, but not with clinical outcomes. In mice, trafficking of anti-PD-L1 Abs to lysosomes in F4/80 + macrophages resulted in sPD-L1 production, which was suppressed by treatment with lysosomal degradation inhibitor chloroquine and macrophage depletion. Conclusion: Anti-PD-L1-mediated lysosomal degradation induces sPD-L1 production, which can serve as an indicator to predict irAE development during anti-PD-L1 treatment., Competing Interests: YI has patent applications for immunopotentiating compositions (WO/2009/0297518, 2011/0081341, 2014/0314714, 2015/0093380, 2015/0197572, 2016/0158356, 2016/0158355, 2017/0051060, and 2020/0062846) and an immune function evaluation method (WO/2019/049974). YI reports research grants from the Japan Society for the Promotion of Science (JP19K07783 and JP22K07262 to YI) and Sysmex Corporation. AG reports consulting fees from MSD, Nippon Kayaku, and Daiichi-Sankyo Company outside the submitted work. MS reports receiving research grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Nippon Kayaku, and Kyowa Hakko Kirin and honoraria from AstraZeneca, MSD, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Pfizer, Novartis, Takeda Pharmaceutical, Kyowa Hakko Kirin, Nippon Kayaku, Daiichi-Sankyo Company, Merck Biopharma, and Amgen outside the submitted work. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Kashiwada, Takano, Ando, Kuroda, Miyabe, Owada, Miyanaga, Asatsuma-Okumura, Hashiguchi, Kanazawa, Yoshida, Seike, Gemma and Iwai.)

Background: The tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade., Methods: We examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients ( n = 117) prior to surgery and NSCLC patients ( n = 72) prior to and 2 months after ICI treatment. We also examined extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25 GC patients by Elastica Masson-Goldner staining and immunohistochemical staining for PD-L1 and CD3, respectively., Results: bsPD-L1 was detected in 17/117 GC patients and 16/72 NSCLC patients. bsPD-L1 showed strong or moderate correlations with plasma MMP13 or MMP3 levels, respectively, in both GC and NSCLC patients. bsPD-L1 expression in GC was associated with IFN-γ levels and intra-tumoral T cell infiltration, whereas MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. Plasma MMP3 and MMP13 levels were altered during ICI treatment. Combined bsPD-L1 and MMP status had higher predictive accuracy to identify two patient groups with favorable and poor prognosis than tumor PD-L1 expression: bsPD-L1 + MMP13 high in GC and bsPD-L1 + (MMP3 and MMP13) increased in NSCLC were associated with poor prognosis, whereas bsPD-L1 + MMP13 low in GC and bsPD-L1 + (MMP3 or MMP13) decreased in NSCLC were associated with favorable prognosis., Conclusion: Plasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC., Competing Interests: YI has patent applications for immunopotentiating compositions (WO/2009/0297518, 2011/0081341, 2014/0314714, 2015/0093380, 2015/0197572, 2016/0158356, 2016/0158355, 2017/0051060, and 2020/0062846) and an immune function evaluation method (WO/2019/049974). YI reports research grants from the Japan Society for the Promotion of Science (JP19K07783 and JP22K07262 to YI) and Sysmex Corporation. AG reports consulting fees from MSD, Nippon Kayaku, and Daiichi-Sankyo Company outside the submitted work. MS reports receiving research grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Nippon Kayaku, and Kyowa Hakko Kirin and honoraria from AstraZeneca, MSD, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Pfizer, Novartis, Takeda Pharmaceutical, Kyowa Hakko Kirin, Nippon Kayaku, Daiichi-Sankyo Company, Merck Biopharma, and Amgen outside the submitted work. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ando, Kashiwada, Kuroda, Fujii, Takano, Miyabe, Kunugi, Sakatani, Miyanaga, Asatsuma-Okumura, Hashiguchi, Kanazawa, Ohashi, Yoshida, Seike, Gemma and Iwai.)

Thalidomide, well known for its potent teratogenicity, has been re-evaluated as a clinically effective drug for the treatment of multiple myeloma. Although the direct target of thalidomide had been unclear until recently, we identified cereblon (CRBN) as a primary direct target of this drug by affinity purification using ferrite glycidyl methacrylate (FG) beads in 2010. CRBN functions as a unique substrate receptor of cullin-RING ligase 4 (CRL4). Various ligands including thalidomide bind to CRBN and alter substrate specificity depending on compound shape, resulting in multiple beneficial effects and/or teratogenicity. Lenalidomide, a thalidomide derivative approved by the US Food and Drug Administration (FDA), induces the degradation of onco-proteins such as Ikaros and casein kinase 1 alpha (CK1α), resulting in anti-cancer effects. Recently, novel CRBN-binding compounds have been developed and their mechanisms of action have been analyzed, including identification of CRBN-related ubiquitin conjugating enzymes (E2s). Moreover, the 3D structure of several CRBN-ligand-substrate complexes has been determined. Ligands were shown to work as a molecular glue between CRBN and its neosubstrate. In addition, investigators have been recently developing CRBN-based proteolysis-targeting chimeras to achieve degradation of proteins of interest. In this review, the molecular mechanisms of classical and new CRBN-based drugs are described, and recent advances in this field are discussed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Posttranslational modification (PTM) of proteins is critical for various cellular processes. However, there are few studies examining PTMs in specific proteins using unbiased approaches. Here we report the attempt to identify the PTMs in peroxisome proliferator-activated receptor γ (PPARγ) proteins using our previously established PTM analysis system. In this study, we identified several PTMs in exogenously expressed PPARγ2 proteins from 293T cells as well as endogenous PPARγ1 proteins from a Caco-2 colon cancer cell line. The identified PTMs include phosphorylation of serine 112 and serine 81 in PPARγ2 and PPARγ1, respectively, both of which are well-known mitogen-activated protein kinase- (MAP kinase-) mediated PTMs in PPARγ proteins, thus confirming our experimental approach. Furthermore, previously unknown PTMs were also identified, demonstrating that this method can be applied to find previously unidentified PTMs in PPARγ proteins and other proteins including nuclear receptors.