EZH2 W113C is a gain-of-function mutation in B-cell lymphoma enabling both PRC2 methyltransferase activation and tazemetostat resistance.

Polycomb repressive complex 2 (PRC2) suppresses gene transcription by methylating lysine 27 of histone H3 (H3K27) and plays critical roles in embryonic development. Among the core PRC2 subunits, EZH2 is the catalytic subunit and EED allosterically activates EZH2 upon binding trimethylated H3K27 (H3K27me3). Activating mutations on Y641, A677, and A687 within the enzymatic SET (Su(Var)3 to 9, Enhancer-of-zeste, and Trithorax) domain of EZH2 have been associated with enhanced H3K27me3 and tumorigenicity of many cancers including B-cell lymphoma and melanoma. To tackle the critical residues outside the EZH2 SET domain, we examined EZH2 mutations in lymphoma from cancer genome databases and identified a novel gain-of-function mutation W113C, which increases H3K27me3 in vitro and in vivo and promotes CDKN2A silencing to a similar level as EZH2 Y641F. Different from other gain-of-function mutations, this mutation is located in the SET-activation loop at the EZH2 N terminus, which stabilizes the SET domain and facilitates substrate binding. This may explain how the W113C mutation increases PRC2 activity. Tazemetostat is a Food and Drug Administration-approved EZH2-binding inhibitor for follicular lymphoma treatment. Intriguingly, the W113C mutation leads to tazemetostat resistance in both H3K27 methylation and tumor proliferation. Another class of allosteric PRC2 inhibitor binding EED overcomes the resistance, effectively decreases H3K27me3, and blocks tumor proliferation in cells expressing EZH2 W113C. As this mutation is originally identified from lymphoma samples, our results demonstrated its activating characteristic and the deleterious consequence, provide insights on PRC2 regulation, and support the continued exploration of treatment optimization for lymphoma patients.

MS or not MS: T2-weighted imaging (T2WI)-based radiomic findings distinguish MS from its mimics.

BACKGROUND: Ischemic vasculopathy, particularly small-vessel disease, may mimic multiple sclerosis (MS) located in the periventricular or subcortical region on magnetic resonance (MR) examinations and should be included in the differential diagnosis of MS-like lesions. OBJECTIVE: To evaluate the performance of a T2-weighted imaging (T2WI)-based radiomic signature to distinguish MS lesions from lesions corresponding to ischemic demyelination, which often mimics MS on MRI. METHODS: A retrospective study was conducted in 38 patients (627 lesions) with MS and 914 patients (2466 lesions) with lesions mimicking ischemic demyelination in the periventricular or subcortical region. All patients underwent 3 T MRI. A total of 472 radiomic features were extracted from the T2WI data of each patient. Intraclass correlation coefficients were used to select the features with excellent stability and repeatability. Then, we used the minimum-redundancy maximum-relevance (mRMR) and least absolute shrinkage and selection operator (LASSO) algorithms for feature selection. After feature selection, various classifiers (including logistic regression, decision tree, AdaBoost, random forest (RF), or support vector machine (SVM)) were trained. The performance of each classifier was validated in the test set by determining the area under the curve (AUC). RESULTS: Nine features were selected to distinguish MS lesions from the similar lesions of ischemic demyelination. The radiomic signature showed a significant difference between the MS and ischemic demyelination patients (p < 0.01). RF and SVM were overfitted. The LASSO logistic regression model was the best-performing radiomic model,with an AUC, accuracy, sensitivity, and specificity of 0.900 (95% CI: 0.883-0.918), 87.0%, 58.9% and 95.2%, respectively, in the training set and 0.828 (95% CI: 0.791-0.864), 87.7%, 53.6% and 94.4%, respectively, in the validation set. CONCLUSION: The T2WI-based radiomic signature can effectively differentiate MS patients from patients with MS-like lesions due to ischemic demyelination.

Development and validation of the Mandarin disyllable recognition test.

CONCLUSION: Given the phonetic balancing across lists and the validation with spectrally degraded speech, the present Mandarin disyllable recognition test (DRT) materials may be useful for assessing speech performance of Mandarin-speaking cochlear implant (CI) users. If combined with the previously developed sentence materials, these materials would help to establish standardized speech perception tests for Mandarin-speaking hearing-impaired (HI) and CI patients. OBJECTIVES: To develop standardized Mandarin DRT materials that can be used to evaluate the speech performance of Mandarin-speaking HI and CI patients, and to establish standardized Mandarin speech perception test materials that include both disyllables and sentences. METHODS: Ten phonetically balanced Mandarin DRT lists were developed. The DRT materials were validated in 8 normal-hearing (NH) subjects listening to unprocessed speech and in 10 NH subjects listening to a 4-channel, sine-wave vocoded acoustic simulation of CI speech processing. Performance with the DRT materials was compared to that with Mandarin sentence materials previously developed by our group. RESULTS: The distribution of vowels, consonants, and tones within each DRT list was similar to that observed across commonly used Chinese characters. There was no significant difference in disyllable word recognition across lists in both unprocessed and four-channel vocoded speech. There was a significant correlation between disyllable and sentence recognition performance.

Development and validation of the Mandarin speech perception test.

Currently there are few standardized speech testing materials for Mandarin-speaking cochlear implant (CI) listeners. In this study, Mandarin speech perception (MSP) sentence test materials were developed and validated in normal-hearing subjects listening to acoustic simulations of CI processing. Percent distribution of vowels, consonants, and tones within each MSP sentence list was similar to that observed across commonly used Chinese characters. There was no significant difference in sentence recognition across sentence lists. Given the phonetic balancing within lists and the validation with spectrally degraded speech, the present MSP test materials may be useful for assessing speech performance of Mandarin-speaking CI listeners.

Mandarin Chinese speech recognition by pediatric cochlear implant users.

OBJECTIVES: Because of difficulties associated with pediatric speech testing, most pediatric cochlear implant (CI) speech studies necessarily involve basic and simple perceptual tasks. There are relatively few studies regarding Mandarin-speaking pediatric CI users' perception of more difficult speech materials (e.g., words and sentences produced by multiple talkers). Difficult speech materials and tests necessarily require older pediatric CI users, who may have different etiologies of hearing loss, duration of deafness, CI experience. The present study investigated how pediatric CI patient demographics influence speech recognition performance with relatively difficult test materials and methods. METHODS: In this study, open-set recognition of multi-talker (two males and two females) Mandarin Chinese disyllables and sentences were measured in 37 Mandarin-speaking pediatric CI users. Subjects were grouped according to etiology of deafness and previous acoustic hearing experience. Group 1 subjects were all congenitally deafened with little-to-no acoustic hearing experience. Group 2 subjects were not congenitally deafened and had substantial acoustic hearing experience prior to implantation. Multiple linear regression analyses were performed within each group using subject demographics such as age at implantation and age at testing. RESULTS: Pediatric CI performance was generally quite good. For Group 1, mean performance was 82.3% correct for disyllables and 82.8% correct for sentences. For Group 2, mean performance was 76.6% correct for disyllables and 84.4% correct for sentences. For Group 1, multiple linear regression analyses showed that age at implantation predicted disyllable recognition, and that age at implantation and age at testing predicted sentence recognition. For Group 2, neither age at implantation nor age at testing predicted disyllable or sentence recognition. Performance was significantly better with the female than with the male talkers. CONCLUSIONS: Consistent with previous studies' findings, early implantation provided a significant advantage for profoundly deaf children. Performance for both groups was generally quite good for the relatively difficult materials and tasks, suggesting that open-set word and sentence recognition may be useful in evaluating speech performance with older pediatric CI users. Differences in disyllable recognition between Groups 1 and 2 may reflect differences in adaptation to electric stimulation. The Group 1 subjects developed speech patterns exclusively via electric stimulation, while the Group 2 subjects adapted to electric stimulation relative to previous acoustic patterns.

Influence of pitch, timbre and timing cues on melodic contour identification with a competing masker (L).

Pitch, timbre, and/or timing cues may be used to stream and segregate competing musical melodies and instruments. In this study, melodic contour identification was measured in cochlear implant (CI) and normal-hearing (NH) listeners, with and without a competing masker; timing, pitch, and timbre cues were varied between the masker and target contour. NH performance was near-perfect across different conditions. CI performance was significantly poorer than that of NH listeners. While some CI subjects were able to use or combine timing, pitch and/or timbre cues, most were not, reflecting poor segregation due to poor spectral resolution.

Relationship between high-resolution computed tomography densitometry and audiometry in otosclerosis.

OBJECTIVE: The aim of this study is to evaluate the usefulness of high-resolution computed tomography (HRCT) densitometry in the diagnosis of otosclerosis and to investigate the relationship between CT densitometry and audiometry. METHODS: HRCT findings and audiometry were compared among 34 patients (34 ears, the otosclerosis group) with surgically confirmed otosclerosis between January 2007 and December 2007 and 33 patients (33 opposite normal ears, the control group) with facial paralysis diagnosed at the same period of time. Seven regions of interest (ROI) were set manually around the otic capsule on the axial slice of 0.75-mm-thick CT image. The mean CT values of these seven regions were measured. In each ROI, the mean CT value of the otosclerosis group and that of the control group were compared. Based on the CT findings, the ears with otosclerosis were classified into two groups: Group A showed no pathological CT findings; Group B showed low density around the cochlea. In the otosclerosis group, the relationship between the findings of CT and the results of audiometry was analyzed. RESULTS: The mean CT values in the area posterior to the oval window and anterior to the oval window were significantly lower for the otosclerosis group compared with the control group (the former t=-2.030, p=0.046; the latter Z=-4.979, p<0.01). Group A consisted of 30 patients, 7 of which (23.33%) exhibited conductive hearing loss, and 23 of which (76.67%) exhibited mixed hearing loss; Group B had 4 patients, all with mixed hearing loss. For the otosclerosis group, the mean CT value in the area posterior to the oval window was positively correlated with the mean air conduction threshold (r=0.4273, p=0.0117) and with the mean air-bone gap (r=0.3995, p=0.0192). CONCLUSION: Quantitative evaluation of CT with slices less than 1mm in thickness may provide important information for the diagnosis and assessment of otosclerosis which are unattainable through other methods.

[In vitro effect of secnidazole benzoate on Trichomonas vaginalis].

OBJECTIVE: To research the trichomonacidal effect of secnidazole benzoate in vitro. METHODS: Trichomonas vaginalis was cultured in liver extract medium in 96-well microplate. The culture suspension of Trichomonas vaginalis was divided into four groups: secnidazole benzoate, secnidazole, metronidazole and control, with medium as blank control. MTT colorimetric assay was applied to determine the inhibitory effect of secnidazole benzoate on the proliferation of Trichomonas vaginalis. The culture suspension was transferred into test tubes and divided into same groups to observe inhibitory effect by the classical microscopic counting method. RESULTS: After 24 h incubation, the proliferation of the parasites was concentration-dependent by secnidazole benzoate (t = 9.02, P < 0.01) at the concentration ranges from 0.15 microg/ml to 20.0 microg/ml with a relative inhibition rate (%) of 14.6, 28.7, 31.3, 60.4, 89.0, 89.2, 95.6, and 100.0 for MTT colorimetric assay, and 18.2, 31.1, 39.7, 68.8, 84.6, 90.1, 94.6, and 100.0 for counting method, respectively. In the period of 6-24 h incubation, the inhibition was in a time-dependent manner. The minimum sterilizing concentration and the minimum inhibitory concentration were 20 microg/ml and 0.15 microg/ml respectively. CONCLUSION: Secnidazole benzoate shows a similar trichomonacidal effect to metronidazole and secnidazole.