New insights for gynecological cancer therapies: from molecular mechanisms and clinical evidence to future directions.

Advanced and recurrent gynecological cancers lack effective treatment and have poor prognosis. Besides, there is urgent need for conservative treatment for fertility protection of young patients. Therefore, continued efforts are needed to further define underlying therapeutic targets and explore novel targeted strategies. Considerable advancements have been made with new insights into molecular mechanisms on cancer progression and breakthroughs in novel treatment strategies. Herein, we review the research that holds unique novelty and potential translational power to alter the current landscape of gynecological cancers and improve effective treatments. We outline the advent of promising therapies with their targeted biomolecules, including hormone receptor-targeted agents, inhibitors targeting epigenetic regulators, antiangiogenic agents, inhibitors of abnormal signaling pathways, poly (ADP-ribose) polymerase (PARP) inhibitors, agents targeting immune-suppressive regulators, and repurposed existing drugs. We particularly highlight clinical evidence and trace the ongoing clinical trials to investigate the translational value. Taken together, we conduct a thorough review on emerging agents for gynecological cancer treatment and further discuss their potential challenges and future opportunities.

A Convolutional Neural Network Model for Distinguishing Hemangioblastomas From Other Cerebellar-and-Brainstem Tumors Using Contrast-Enhanced MRI.

BACKGROUND: Hemangioblastoma (HB) is a highly vascularized tumor most commonly occurring in the posterior cranial fossa, requiring accurate preoperative diagnosis to avoid accidental intraoperative hemorrhage and even death. PURPOSE: To accurately distinguish HBs from other cerebellar-and-brainstem tumors using a convolutional neural network model based on a contrast-enhanced brain MRI dataset. STUDY TYPE: Retrospective. POPULATION: Four hundred five patients (182 = HBs; 223 = other cerebellar-and brainstem tumors): 305 cases for model training, and 100 for evaluation. FIELD STRENGTH/SEQUENCE: 3 T/contrast-enhanced T1-weighted imaging (T1WI + C). ASSESSMENT: A CNN-based 2D classification network was trained by using sliced data along the z-axis. To improve the performance of the network, we introduced demographic information, various data-augmentation methods and an auxiliary task to segment tumor region. Then, this method was compared with the evaluations performed by experienced and intermediate-level neuroradiologists, and the heatmap of deep feature, which indicates the contribution of each pixel to model prediction, was visualized by Grad-CAM for analyzing the misclassified cases. STATISTICAL TESTS: The Pearson chi-square test and an independent t-test were used to test for distribution difference in age and sex. And the independent t-test was exploited to evaluate the performance between experts and our proposed method. P value <0.05 was considered significant. RESULTS: The trained network showed a higher accuracy for identifying HBs (accuracy = 0.902 ± 0.031, F1 = 0.891 ± 0.035, AUC = 0.926 ± 0.040) than experienced (accuracy = 0.887 ± 0.013, F1 = 0.868 ± 0.011, AUC = 0.881 ± 0.008) and intermediate-level (accuracy = 0.827 ± 0.037, F1 = 0.768 ± 0.068, AUC = 0.810 ± 0.047) neuroradiologists. The recall values were 0.910 ± 0.050, 0.659 ± 0.084, and 0.828 ± 0.019 for the trained network, intermediate and experienced neuroradiologists, respectively. Additional ablation experiments verified the utility of the introduced demographic information, data augmentation, and the auxiliary-segmentation task. DATA CONCLUSION: Our proposed method can successfully distinguish HBs from other cerebellar-and-brainstem tumors and showed diagnostic efficiency comparable to that of experienced neuroradiologists. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Correlations between intravoxel incoherent motion-derived fast diffusion and perfusion fraction parameters and VEGF- and MIB-1-positive rates in brain gliomas: an intraoperative MR-navigated, biopsy-based histopathologic study.

OBJECTIVES: To explore the correlations between histopathologic findings and intravoxel incoherent motion (IVIM)-derived perfusion and diffusion parameters in brain gliomas. METHODS: Thirty-two biopsy samples from twenty-one patients with newly diagnosed gliomas from a previous prospective cohort study were retrospectively analyzed. All patients underwent diffusion-weighted MRI with 22 b values (0-5000 s/mm2), followed by intraoperative MR-guided biopsy surgery and surgical resection. All 32 biopsy samples underwent immunohistochemical staining followed by quantitative analysis of cell density (cellularity), percent of MIB-1 (Ki67)-positive expression (pMIB-1), number of CD34-stained vessels (CD34-MVD), and percent of VEGF-positive expressing cells (pVEGF) using a multispectral phenotyping microscope. Based on the co-registered localized biopsy, correlation analysis was performed between the IVIM-derived biexponential model-based parameters (Dfast1500 and Dfast5000, Dslow1500 and Dslow5000, PF1500 and PF5000) and the above four pathological biomarkers and glioma grades. RESULTS: Significant positive correlations were revealed between Dfast5000 and pVEGF (rho (r) = 0.466, p = 0.007), and Dfast1500 and pVEGF (r = 0.371, p = 0.037). A significant negative correlation was revealed between PF5000 with pMIB-1 (r = - 0.456, p = 0.01). Moderate to good positive correlations were shown between Dfast5000 and glioma grades (r = 0.509, p = 0.003) and Dfast1500 and glioma grades (r = 0.476, p = 0.006). CONCLUSIONS: IVIM-DWI-derived Dfast and PF correlate, respectively, with intratumor pVEGF and pMIB-1. When using the wide-high b value scheme, IVIM-derived Dfast and PF tend to demonstrate better efficacy in evaluating malignancy-related characteristics such as angiogenesis and cellular proliferation in gliomas. KEY POINTS: • Intravoxel incoherent motion-diffusion-weighted imaging (IVIM-DWI)-derived fast diffusion (Dfast) and perfusion fraction (PF) can quantitatively reflect intratumor pVEGF and pMIB-1. • IVIM-DWI-derived Dfast and PF tend to demonstrate better efficacy in evaluating glioma malignancy when an optimized scheme is used. • IVIM-DWI-derived Dfast5000 and PF5000 are promising non-invasive parameters correlating with pVEGF and pMIB-1 in gliomas.

An Accurate and Individualized Preoperative Estimation Method for the Linear Insertion Depth of Cochlear Implant Electrode Arrays Based on Computed Tomography.

OBJECTIVES: Cochlear implantation or auditory brainstem implantation is currently the only accepted method for improving severe or profound sensorineural hearing loss. The length of the electrodes implanted during cochlear implantation is closely related to the degree of hearing improvement of hearing after the surgery. We aimed to explore new methods to accurately estimate the electrode array (EA) linear insertion depth based on computed tomography (CT) images prior surgery, which could help surgeons select the appropriate EA length for each patient. DESIGN: Previous studies estimated the linear insertion depth by measuring the length of the lateral wall of the cochlea rather than the electrode's path in the cochlea duct. Here, we determined the actual position of the EA on the CT image after cochlear surgery in order to predict the path of the EA, and the length of the predicted EA path was measured by the contouring technique (CoT) to estimate the linear insertion depth of the EA. Because CoT can only measure the length of the estimated EA path on a two-dimensional plane, we further modified the measurement by weighting the height of the cochlea and the length of the EA tail (the length of the last stimulating electrode to the end, which cannot be displayed on the CT image), which we termed the modified CoT + height + tail (MCHT) measurement. RESULTS: Based on our established method, MCHT could reduce the error to the submillimeter range (0.67 ± 0.37 mm) when estimating the linear insertion depth of various kinds of EAs compared with the actual implant length. The correlation coefficient between the linear insertion depth as predicted by MCHT and the actual was 0.958. The linear insertion depth estimated by this method was more accurate than that estimated using the classical CoT technique ( R = 0.442) and using the modified Escudé's method ( R = 0.585). CONCLUSIONS: MCHT is a method based on CT images that can accurately predict the linear insertion depth of cochlear implants preoperatively. This is the first report that we are aware of a method for predicting linear insertion depth before cochlear implantation with only submillimeter errors and that is tailored to different types of EAs.

A nomogram strategy for identifying the subclassification of IDH mutation and ATRX expression loss in lower-grade gliomas.

OBJECTIVES: To construct a radiomics nomogram based on multiparametric MRI data for predicting isocitrate dehydrogenase 1 mutation (IDH +) and loss of nuclear alpha thalassemia/mental retardation syndrome X-linked expression (ATRX -) in patients with lower-grade gliomas (LrGG; World Health Organization [WHO] 2016 grades II and III). METHODS: A total of 111 LrGG patients (76 mutated IDH and 35 wild-type IDH) were enrolled, divided into a training set (n = 78) and a validation set (n = 33) for predicting IDH mutation. IDH + LrGG patients were further stratified into the ATRX - (n = 38) and ATRX + (n = 38) subtypes. A total of 250 radiomics features were extracted from the region of interest of each tumor, including that from T2 fluid-attenuated inversion recovery (T2 FLAIR), contrast-enhanced T1 WI, ASL-derived cerebral blood flow (CBF), DWI-derived ADC, and exponential ADC (eADC). A radiomics signature was selected using the Elastic Net regression model, and a radiomics nomogram was finally constructed using the age, gender information, and above features. RESULTS: The radiomics nomogram identified LrGG patients for IDH mutation (C-index: training sets = 0.881, validation sets = 0.900) and ATRX loss (C-index: training sets = 0.863, validation sets = 0.840) with good calibration. Decision curve analysis further confirmed the clinical usefulness of the two nomograms for predicting IDH and ATRX status. CONCLUSIONS: The nomogram incorporating age, gender, and the radiomics signature provided a clinically useful approach in noninvasively predicting IDH and ATRX mutation status for LrGG patients. The proposed method could facilitate MRI-based clinical decision-making for the LrGG patients. KEY POINTS: • Non-invasive determination of IDH and ATRX gene status of LrGG patients can be obtained with a radiomics nomogram. • The proposed nomogram is constructed by radiomics signature selected from 250 radiomics features, combined with age and gender. • The proposed radiomics nomogram exhibited good calibration and discrimination for IDH and ATRX gene mutation stratification of LrGG patients in both training and validation sets.

Detection of cholesteatoma: 2D BLADE turbo gradient- and spin-echo imaging versus readout-segmented echo-planar diffusion-weighted imaging.

PURPOSE: This study is to compare the accuracy of 2D BLADE turbo gradient- and spin-echo imaging (TGSE BLADE) diffusion-weighted imaging (DWI) with that of readout-segmented echo-planar (RESOLVE) DWI in the detection of primary and residual/recurrent temporal bone cholesteatoma. METHODS: The prospective study population consisted of 58 patients who were underwent magnetic resonance (MR) imaging for the evaluation of suspected temporal bone cholesteatoma. Two radiologists independently evaluated the two sequences. Kappa (k) statistics, the intra-class correlation coefficient (ICC), and a paired t test were used for statistical analysis. RESULTS: Of the 58 patients included, all had histo-pathologically confirmed cholesteatomas. In ≤ 3 mm group (n = 13), TGSE BLADE sequence correctly identified all cases except one that was recorded as equivocal on both sequences because of high signal intensity on T1WI; while on RESOLVE sequences, 6 were positive, 4 were equivocal, and 3 were false negative. For > 3 mm group (n = 45), detection performance was similar between the two sequences. The mean ADC of cholesteatoma on TGSE BLADE DWI was 0.923 × 10-3 mm2/s, and the mean ADC of cholesteatoma on RESOLVE DWI was 0.949 × 10-3 mm2/s, with no significant difference in the mean ADC values of cholesteatoma measured on the two sequences (p = 0.9216). CONCLUSION: TGSE BLADE outperforms RESOLVE in the detection of small temporal bone cholesteatoma ≤ 3 mm.

E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo.

Cell polarity and correct mitotic spindle positioning are essential for the maintenance of a proper prostate epithelial architecture, and disruption of the two biological features occurs at early stages in prostate tumorigenesis. However, whether and how these two epithelial attributes are connected in vivo is largely unknown. We herein report that conditional genetic deletion of E-cadherin, a key component of adherens junctions, in a mouse model results in loss of prostate luminal cell polarity and randomization of spindle orientations. Critically, E-cadherin ablation causes prostatic hyperplasia which progresses to invasive adenocarcinoma. Mechanistically, E-cadherin and the spindle positioning determinant LGN interacts with the PDZ domain of cell polarity protein SCRIB and form a ternary protein complex to bridge cell polarity and cell division orientation. These findings provide a novel mechanism by which E-cadherin acts an anchor to maintain prostate epithelial integrity and to prevent carcinogenesis in vivo.

Performance of TGSE BLADE DWI compared with RESOLVE DWI in the diagnosis of cholesteatoma.

BACKGROUND: Based on its high resolution in soft tissue, MRI, especially diffusion-weighted imaging (DWI), is increasingly important in the evaluation of cholesteatoma. The purpose of this study was to evaluate the role of the 2D turbo gradient- and spin-echo (TGSE) diffusion-weighted (DW) pulse sequence with the BLADE trajectory technique in the diagnosis of cholesteatoma at 3 T and to qualitatively and quantitatively compare image quality between the TGSE BLADE and RESOLVE methods. METHOD: A total of 42 patients (23 males, 19 females; age range, 7-65 years; mean, 40.1 years) with surgically confirmed cholesteatoma in the middle ear were enrolled in this study. All patients underwent DWI (both a prototype TGSE BLADE DWI sequence and the RESOLVE DWI sequence) using a 3-T scanner with a 64-channel brain coil. Qualitative imaging parameters (imaging sharpness, geometric distortion, ghosting artifacts, and overall imaging quality) and quantitative imaging parameters (apparent diffusion coefficient [ADC], signal-to-noise ratio [SNR], contrast, and contrast-to-noise ratio [CNR]) were assessed for the two diffusion acquisition techniques by two independent radiologists. RESULT: A comparison of qualitative scores indicated that TGSE BLADE DWI produced less geometric distortion, fewer ghosting artifacts (P < 0.001) and higher image quality (P < 0.001) than were observed for RESOLVE DWI. A comparison of the evaluated quantitative image parameters between TGSE and RESOLVE showed that TGSE BLADE DWI produced a significantly lower SNR (P < 0.001) and higher parameter values (both contrast and CNR (P < 0.001)) than were found for RESOLVE DWI. The ADC (P < 0.001) was significantly lower for TGSE BLADE DWI (0.763 × 10- 3 mm2/s) than RESOLVE DWI (0.928 × 10- 3 mm2/s). CONCLUSION: Compared with RESOLVE DWI, TGSE BLADE DWI significantly improved the image quality of cholesteatoma by reducing magnetic sensitive artifacts, distortion, and blurring. TGSE BLADE DWI is more valuable than RESOLVE DWI for the diagnosis of small-sized (2 mm) cholesteatoma lesions. However, TGSE BLADE DWI also has some disadvantages: the whole image intensity is slightly low, so that the anatomical details of the air-bone interface are not shown well, and this shortcoming should be improved in the future.

Increased IGF2BP3 expression promotes the aggressive phenotypes of colorectal cancer cells in vitro and vivo.

Previous literatures reported insulin-like growth factor-2 messenger RNA-binding protein 3 (IGF2BP3) is a poor prognostic marker for colorectal cancer (CRC) patients. However, basic research on the effect and biological role of IGF2BP3 in CRC was still scare. Real-time quantitative polymerase chain reaction and western blot analysis were used to examine IGF2BP3 expression level in tumors and paired normal tissues from CRC patients. Tissue microarrays with 192 CRC patients were subjected to immunohistochemical staining to analyze the prognostic value of IGF2BP3. Proliferation assays, migration assays, and xenograft tumor formation in nude mice were performed to assess the biological role of IGF2BP3 in CRC cells. IGF2BP3 expression was significantly upregulated in tumor tissues compared with the matched normal tissues both in messenger RNA and protein level and was associated with worse prognosis. IGF2BP3 knockdown made cell cycle arrest to impair the proliferation ability of CRC cells and further inhibited the xenograft tumor growth in nude mice, also inhibited the migration ability of CRC cells via inducing epithelial-mesenchymal transition. Therefore, the research demonstrated that increased IGF2BP3 expression promoted the aggressive phenotypes of CRC cells. Targeted IGF2BP3 could be a novel and effective gene therapy for CRC patients to make a better prognosis.

A data-driven intravoxel mean diffusivities distribution approach for molecular classifications and MIB-1 prediction of gliomas.

BACKGROUND: Measuring non-parametric intravoxel mean diffusivity distributions (MDDs) using magnetic resonance imaging (MRI) is a sensitive method for detecting intracellular diffusivity changes during physiological alterations. Histological and molecular glioma classifications are essential for prognosis and treatment, with distinct water diffusion dynamics among subtypes. PURPOSE: We developed a data-driven approach using a fully connected network (FCN) to enhance the speed and stability of calculating MDDs across varying SNRs, enable tumor microstructural mapping, and test its reliability in identifying MIB-1 labeling index (LI) levels and molecular status of gliomas. METHODS: An FCN was trained to learn the mapping between the simulated diffusion decay curves and the ground truth MDDs. We performed 5 000 000 simulation curves with various diffusivity components and random SNR ∈ [ 30 , 300 ] $ \in [ {30,\ 300} ]$ . Eighty percent of simulation curves were used for the FCN training, 10% for validation, and the others were external tests for the FCN performance evaluation. In vivo data were collected to evaluate its clinical reliability. One hundred one patients (44 years ± $ \pm $ 14, 67 men) with gliomas and six healthy controls underwent a 3.0 T MRI examination with a spin echo-echo planar imaging (SE-EPI) diffusion-weighted imaging (DWI) sequence. The trained FCN was employed to calculate MDDs of each brain voxel by voxel. We used the Fuzzy C-means algorithm to cluster the MDDs of tumor voxels, facilitating the characterization of distinct glioma tissues. Quantitative assessments were conducted through sectional integrals of the MDDs, demarcated by six bands to derive signal fractions ( f n , n = 1 - 6 ${{f}_n},\ n = 1 -6$ ) and diffusivities of the maximum peaks ( D p e a k ${{D}_{peak}}$ ). Cosine similarity scores (CSS) were used for MDD similarity. ANOVA and Mann-Whitney U test were used for difference analysis. Logistic regression and area under the receiver operator characteristic curve (AUC) were used for classification evaluation. RESULTS: The simulation results showed that the FCN-based MDD approach (FCN-MDD) achieved higher CSS than non-negative least squares-based MDD (NNLS-MDD). For in vivo data, the spectra of ET and NET obtained by FCN-MDD are more distinguishable than NNLS-MDD. Fraction maps delineate the characteristics of different tumor tissues (enhancing and non-enhancing tumor, edema, and necrosis). f 3 , f 4 , D p e a k ${{f}_3},\ {{f}_4},{{D}_{peak}}$ showed a positive and negative correlation with MIB-1 respectively ( r = 0.568 , r = - 0.521 , r = - 0.654 $r = 0.568,\ r = - 0.521,\ r = - 0.654$ , all p < 0.001 $p < 0.001$ ). The AUC of D p e a k ${{D}_{peak}}$ for predicting MIB-1 LI levels was 0.900 (95% CI, 0.826-0.974), versus 0.781 (0.677-0.886) of ADC. The highest AUC of isocitrate dehydrogenase (IDH) mutation status, assessed by a logistic regression model ( f 1 + f 3 ${{f}_1} + {{f}_3}$ ) was 0.873 (95% CI, 0.802-0.944). CONCLUSION: The proposed FCN-MDD method was more robust to variations in SNR and less reliant on empirically set regularization values than the NNLS-MDD method. FCN-MDD also enabled qualitative and quantitative evaluation of the composition of gliomas.

Low-grade Papillary Nasopharyngeal Adenocarcinoma: A Clinicopathologic Series of 35 Cases.

Low-grade nasopharyngeal papillary adenocarcinoma (LGNPPA) is a rare neoplasm originating from the surface mucosal epithelium in the nasopharynx. To clarify its clinicopathologic, immunohistochemical, and molecular features, we retrospectively enrolled 35 patients diagnosed with LGNPPA between May 2016 and March 2024. Our cohort consisted of 14 male and 21 female patients aged 11 to 71 years (median: 37 y). The most common symptoms were rhinorrhea and nasal obstruction. Most tumors originated from the roof of the nasopharynx and were clinically staged as T1N0M0. None of the patients had a history of thyroid tumors. Microscopically, most of the LGNPPA were composed of irregular papillary structures covered with single-layer columnar or cuboidal epithelium. Eighteen cases (18/35, 51.4%) showed squamous epithelium coverage, and 9 cases (9/35, 25.7%) showed the characteristic transformation of squamous epithelium into neoplasm. Squamous differentiation and a significant spindle cell component were noted in 9 cases (9/35, 25.7%) and 26 cases (26/35, 74.3%), respectively. All cases were positive for thyroid transcription factor-1 protein, CK7, EMA, and Galectin-3 but negative for thyroglobulin, PAX8, and Napsin A. Ki-67 labeling was low and ranged from 2% to 5%. The Epstein-Barr virus or human papilloma virus infection and BRAF V600E mutation were not detected in any of the cases. All patients underwent endoscopic surgical resection, and 4 patients received radiotherapy followed by endoscopic surgery. Complete follow-up data were available for 33 patients. All patients had no recurrent or metastatic disease in the last follow-up (3 to 88 mo). A definitive diagnosis depends on histopathology and immunohistochemistry studies. The optimal treatment for patients with LGNPPA is total excision. Given the extremely indolent biological behavior of LGNPPA, it may be more appropriate to classify it as a primary papillary epithelial tumor rather than an adenocarcinoma of the nasopharynx.

Deep Learning-Assisted Quantitative Susceptibility Mapping as a Tool for Grading and Molecular Subtyping of Gliomas.

This study aimed to explore the value of deep learning (DL)-assisted quantitative susceptibility mapping (QSM) in glioma grading and molecular subtyping. Forty-two patients with gliomas, who underwent preoperative T2 fluid-attenuated inversion recovery (T2 FLAIR), contrast-enhanced T1-weighted imaging (T1WI + C), and QSM scanning at 3.0T magnetic resonance imaging (MRI) were included in this study. Histopathology and immunohistochemistry staining were used to determine glioma grades, and isocitrate dehydrogenase (IDH) 1 and alpha thalassemia/mental retardation syndrome X-linked gene (ATRX) subtypes. Tumor segmentation was performed manually using Insight Toolkit-SNAP program (www.itksnap.org). An inception convolutional neural network (CNN) with a subsequent linear layer was employed as the training encoder to capture multi-scale features from MRI slices. Fivefold cross-validation was utilized as the training strategy (seven samples for each fold), and the ratio of sample size of the training, validation, and test dataset was 4:1:1. The performance was evaluated by the accuracy and area under the curve (AUC). With the inception CNN, single modal of QSM showed better performance in differentiating glioblastomas (GBM) and other grade gliomas (OGG, grade II-III), and predicting IDH1 mutation and ATRX loss (accuracy: 0.80, 0.77, 0.60) than either T2 FLAIR (0.69, 0.57, 0.54) or T1WI + C (0.74, 0.57, 0.46). When combining three modalities, compared with any single modality, the best AUC/accuracy/F1-scores were reached in grading gliomas (OGG and GBM: 0.91/0.89/0.87, low-grade and high-grade gliomas: 0.83/0.86/0.81), predicting IDH1 mutation (0.88/0.89/0.85), and predicting ATRX loss (0.78/0.71/0.67). As a supplement to conventional MRI, DL-assisted QSM is a promising molecular imaging method to evaluate glioma grades, IDH1 mutation, and ATRX loss. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00087-6.

Accuracy of 2D BLADE Turbo Gradient- and Spin-Echo Diffusion Weighted Imaging for the Diagnosis of Primary Middle Ear Cholesteatoma.

OBJECTIVE: To evaluate the diagnostic accuracy of 2D BLADE turbo gradient- and spin-echo diffusion weighted imaging (TGSE BLADE DWI) for primary middle ear cholesteatoma diagnosis, using qualitative and quantitative methods. STUDY DESIGN: Retrospective case series. SETTING: University hospital. PATIENTS: Participants included those with suspected primary middle ear cholesteatoma after assessment by clinical otorhinolaryngologists combined with magnetic resonance imaging (MRI) examination. Finally, of the 85 ears from 65 patients enrolled in the study, 73 had cholesteatoma, and 12 had otitis media. INTERVENTION: Two radiologists independently assessed images and measured apparent diffusion coefficient (ADC) values. Sensitivity, specificity and accuracy were evaluated. Kappa (k) statistics, the intraclass correlation coefficient (ICC), the Kolmogorov-Smirnov normality test, the independent t test, and receiver operating characteristic (ROC) analysis were used for statistical analysis. Pair-wise comparison of the area under the ROC curve (AUC) was also performed using the Delong test. MAIN OUTCOME MEASURES: Imaging and histopathologic findings. RESULTS: The mean ADC value of cholesteatoma group (mean, 0.923 ± 0.246 × 10 -3 mm 2 /s) was significantly lower than that of noncholesteatoma group (mean, 1.744 ± 0.205 × 10 -3 mm 2 /s; p < 0.001). In ≤3 mm cholesteatoma group, the AUC of qualitative DWI was 0.846; the sensitivity, specificity, and accuracy for diagnosing cholesteatoma were 69.23%, 100%, and 84%, respectively; while the AUC of quantitative diagnosis was significantly increased to 1.0 ( p = 0.0209); and based on the optimal threshold of ADC, ≤1.352 × 10 -3 mm 2 /s, the sensitivity, specificity and accuracy improved to 100%. For >3 mm cholesteatoma group, there were no significant differences in diagnostic performance. Excellent interobserver agreement and ICC for the qualitative and quantitative evaluations (k = 0.90 and ICC = 0.80, respectively) was noted between reviewers. CONCLUSION: TGSE BLADE DWI is useful for the detection of primary middle ear cholesteatomas, especially ≤3 mm lesions.

Ovarian Mature Cystic Teratoma is an Independent Risk Factor for the Premature Rupture of Membranes in Pregnancy: A Single-Center Retrospective Study.

Background: Ovarian mature cystic teratomas (MCTs) are the most common tumors in pregnant women. The premature rupture of membranes (PROM) is a typical complication of pregnancy; however, the relationship between MCT and PROM is unknown. Therefore, we aimed to determine whether MCT is associated with the occurrence of PROM during pregnancy. Methods: The data of patients with adnexal masses during pregnancy between January 2017 and August 2021 were retrospectively analyzed. Ovarian cystectomy was performed during cesarean delivery or after vaginal delivery. Univariate and multivariate logistic regression models were used for statistical analysis. Results: A total of 234 patients with histopathological results were included. Among these patients, 21 occurred PROM during pregnancy, of which 11 were diagnosed with MCT. Compared with other subtypes, MCT (p=0.025) showed a stronger correlation with PROM and was an independent risk factor for PROM (odds ratio [OR], 2.811; 95% confidence interval [CI], 1.096-7.215; p=0.032). Furthermore, we found that MCT with a diameter >5 cm (p=0.0037) was more likely to promote the development of PROM than those that with a diameter <5 cm. Conclusion: MCT was an independent risk factor for PROM during pregnancy. Positive actions and preventative clinical treatments should be fully taken into consideration by clinicians for pregnant women with MCTs, especially those ≥5 cm in diameter, to reduce the clinical complications related to MCT-associated PROM.

Zeb1 sustains hematopoietic stem cell functions by suppressing mitofusin-2-mediated mitochondrial fusion.

Metabolic status is essential in maintaining normal functions of hematopoietic stem cells (HSCs). However, how the dynamic of the mitochondrion, as a central organelle in metabolism, is molecularly regulated to orchestrate metabolism and HSC stemness remains to be elucidated. Here, we focus on the role of Zeb1, a well-characterized epithelial-to-mesenchymal transition (EMT) inducer which has been demonstrated to confer stem-cell-like characteristics in multiple cancer types in stemness regulation of HSCs. Using a Zeb1-tdTomato reporter mouse model, we find that Zeb1+Lin-Sca-1+c-Kit+ cells (Zeb1+-LSKs) represent a subset of functional long-term HSCs. Zeb1+LSKs exhibit a reduced reactive oxygen species (ROS) level, low mitochondrial mass, low mitochondrial membrane potential (MMP), and particularly small, round fragmented mitochondria. Of note, ectopic expression of Zeb1 leads to a fragmented mitochondrial morphology with a low mitochondrial metabolic status in EML cells. In addition, Zeb1-knockout (Zeb1-KO) LSKs from fetal liver display an exhausted stem-cell activity. Zeb1 deficiency results in elongated and tubulated mitochondria with increased mitochondrial mass, elevated MMP, and higher ROS production. Mechanistically, Zeb1 acts as a transcriptional suppressor on the key mitochondrial-fusion protein Mitofusin-2 (encoded by Mfn2). We highlight an important role of Zeb1 in the regulation of mitochondrial morphology in HSC and the metabolic control of HSC stemness by repressing Mfn2-mediated mitochondrial fusion.

Identification of a Zeb1 expressing basal stem cell subpopulation in the prostate.

The basal cell compartment in many epithelial tissues is generally believed to serve as an important pool of stem cells. However, basal cells are heterogenous and the stem cell subpopulation within basal cells is not well elucidated. Here we uncover that the core epithelial-to-mesenchymal transition (EMT) inducer Zeb1 is expressed in a prostate basal cell subpopulation. The Zeb1+ prostate epithelial cells are multipotent prostate basal stem cells (PBSCs) that can self-renew and generate functional prostatic glandular structures at the single-cell level. Genetic ablation studies reveal an indispensable role for Zeb1 in prostate basal cell development. Utilizing unbiased single-cell transcriptomic analysis of over 9000 mouse prostate basal cells, we confirm the existence of the Zeb1+ basal cell subset. Moreover, Zeb1+ epithelial cells can be detected in mouse and human prostate tumors. Identification of the PBSC and its transcriptome profile is crucial to advance our understanding of prostate development and tumorigenesis.

Comprehensive comparison of MR image quality between intratympanic and intravenous gadolinium injection using 3D real IR sequences.

Background: Intratympanic and intravenous gadolinium administration is used to visualise endolymphatic hydrops. Aims/objectives: The goal of this study was to compare the image quality between intratympanic (IT-method) and intravenous (IV-method) gadolinium administration using three-dimensional inversion recovery with real reconstruction (3D real IR) sequences. Materials and methods: A number of 152 patients with Meniere's disease were included. The 3D real IR sequence was performed 24 h after IT administration or 4 h after IV administration. The detection rate of endolymphatic hydrops, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) of the two methods were compared. Specifically, the average image scores of the two methods were evaluated by two radiologists. Results: The SNRROI and CNRs of the IT-method were higher than those of the IV-method, whereas no significant difference between the IT-method and IV-method with regard to the SNRB was found. The average image scores were 3.49 ± 0.12 and 3.30 ± 0.12 for the IT-method and IV-method, respectively (p = .229). No statistically significant difference was found between two methods in terms of the detection rate of endolymphatic hydrops. Conclusions and significance: IT-method images can display endolymphatic hydrops more precisely than IV-method images. The IV-method can be used as an alternative to the IT-method in clinical applications to some extent.

Downregulation of the histone methyltransferase SETD2 promotes imatinib resistance in chronic myeloid leukaemia cells.

OBJECTIVES: Epigenetic modifiers were important players in the development of haematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyses the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukaemia progression and resistance to therapy targeting on BCR-ABL remain unclear. MATERIALS AND METHODS: The level of SETD2 in imatinib-sensitive and imatinib-resistant chronic myeloid leukaemia (CML) cells was examined by immunoblotting and quantitative real-time PCR. We analysed CD34+ CD38- leukaemic stem cells by flow cytometry and colony formation assays upon SETD2 knockdown or overexpression. The impact of SETD2 expression alterations or small-molecule inhibitor JIB-04 targeting H3K36me3 loss on imatinib sensitivity was assessed by IC50, cell apoptosis and proliferation assays. Finally, RNA sequencing and ChIP-quantitative PCR were performed to verify putative downstream targets. RESULTS: SETD2 was found to act as a tumour suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukaemic stem cell enrichment in CML cell lines. Treatment with JIB-04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell imatinib sensitivity and enhanced the chemotherapeutic effect. CONCLUSIONS: Our study not only emphasizes the regulatory mechanism of SETD2 in CML, but also provides promising therapeutic strategies for overcoming the imatinib resistance in patients with CML.

The histone methyltransferase Setd2 is indispensable for V(D)J recombination.

The diverse repertoire of T cell receptors (TCR) and immunoglobulins is generated through the somatic rearrangement of respective V, D and J gene segments, termed V(D)J recombination, during early T or B cell development. However, epigenetic regulation of V(D)J recombination is still not fully understood. Here we show that the deficiency of Setd2, a histone methyltransferase that catalyzes lysine 36 trimethylation on histone 3 (H3K36me3) in mice, causes a severe developmental block of thymocytes at the CD4-CD8- DN3 stage. While H3K36me3 is normally enriched at the TCRß locus, Setd2 deficiency reduces TCRß H3K36me3 and suppresses TCRß V(D)J rearrangement by impairing RAG1 binding to TCRß loci and the DNA double-strand break repair. Similarly, Setd2 ablation also impairs immunoglobulin V(D)J rearrangement to induce B cell development block at the pro-B stage. Lastly, SETD2 is frequently mutated in patients with primary immunodeficiency. Our study thus demonstrates that Setd2 is required for optimal V(D)J recombination and normal lymphocyte development.