HPV integration generates a cellular super-enhancer which functions as ecDNA to regulate genome-wide transcription.

Human papillomavirus (HPV) integration is a critical step in cervical cancer development; however, the oncogenic mechanism at the genome-wide transcriptional level is still poorly understood. In this study, we employed integrative analysis on multi-omics data of six HPV-positive and three HPV-negative cell lines. Through HPV integration detection, super-enhancer (SE) identification, SE-associated gene expression and extrachromosomal DNA (ecDNA) investigation, we aimed to explore the genome-wide transcriptional influence of HPV integration. We identified seven high-ranking cellular SEs generated by HPV integration in total (the HPV breakpoint-induced cellular SEs, BP-cSEs), leading to intra-chromosomal and inter-chromosomal regulation of chromosomal genes. The pathway analysis revealed that the dysregulated chromosomal genes were correlated to cancer-related pathways. Importantly, we demonstrated that BP-cSEs existed in the HPV-human hybrid ecDNAs, explaining the above transcriptional alterations. Our results suggest that HPV integration generates cellular SEs that function as ecDNA to regulate unconstrained transcription, expanding the tumorigenic mechanism of HPV integration and providing insights for developing new diagnostic and therapeutic strategies.

Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections.

BRDT, BRD2, BRD3, and BRD4 comprise the bromodomain and extraterminal (BET) subfamily which contain two similar tandem bromodomains (BD1 and BD2). Selective BD1 inhibition phenocopies effects of tandem BET BD inhibition both in cancer models and, as we and others have reported of BRDT, in the testes. To find novel BET BD1 binders, we screened >4.5 billion molecules from our DNA-encoded chemical libraries with BRDT-BD1 or BRDT-BD2 proteins in parallel. A compound series enriched only by BRDT-BD1 was resynthesized off-DNA, uncovering a potent chiral compound, CDD-724, with >2,000-fold selectivity for inhibiting BRDT-BD1 over BRDT-BD2. CDD-724 stereoisomers exhibited remarkable differences in inhibiting BRDT-BD1, with the R-enantiomer (CDD-787) being 50-fold more potent than the S-enantiomer (CDD-786). From structure­activity relationship studies, we produced CDD-956, which maintained picomolar BET BD1 binding potency and high selectivity over BET BD2 proteins and had improved stability in human liver microsomes over CDD-787. BROMOscan profiling confirmed the excellent pan-BET BD1 affinity and selectivity of CDD-787 and CDD-956 on BD1 versus BD2 and all other BD-containing proteins. A cocrystal structure of BRDT-BD1 bound with CDD-956 was determined at 1.82 Å and revealed BRDT-BD1­specific contacts with the αZ and αC helices that explain the high affinity and selectivity for BET BD1 versus BD2. CDD-787 and CDD-956 maintain cellular BD1-selectivity in NanoBRET assays and show potent antileukemic activity in acute myeloid leukemia cell lines. These BET BD1-specific and highly potent compounds are structurally unique and provide insight into the importance of chirality to achieve BET specificity.

DeepHPV: a deep learning model to predict human papillomavirus integration sites.

Human papillomavirus (HPV) integrating into human genome is the main cause of cervical carcinogenesis. HPV integration selection preference shows strong dependence on local genomic environment. Due to this theory, it is possible to predict HPV integration sites. However, a published bioinformatic tool is not available to date. Thus, we developed an attention-based deep learning model DeepHPV to predict HPV integration sites by learning environment features automatically. In total, 3608 known HPV integration sites were applied to train the model, and 584 reviewed HPV integration sites were used as the testing dataset. DeepHPV showed an area under the receiver-operating characteristic (AUROC) of 0.6336 and an area under the precision recall (AUPR) of 0.5670. Adding RepeatMasker and TCGA Pan Cancer peaks improved the model performance to 0.8464 and 0.8501 in AUROC and 0.7985 and 0.8106 in AUPR, respectively. Next, we tested these trained models on independent database VISDB and found the model adding TCGA Pan Cancer performed better (AUROC: 0.7175, AUPR: 0.6284) than the model adding RepeatMasker peaks (AUROC: 0.6102, AUPR: 0.5577). Moreover, we introduced attention mechanism in DeepHPV and enriched the transcription factor binding sites including BHLHA15, CHR, COUP-TFII, DMRTA2, E2A, HIC1, INR, NPAS, Nr5a2, RARa, SCL, Snail1, Sox10, Sox3, Sox4, Sox6, STAT6, Tbet, Tbx5, TEAD, Tgif2, ZNF189, ZNF416 near attention intensive sites. Together, DeepHPV is a robust and explainable deep learning model, providing new insights into HPV integration preference and mechanism. Availability: DeepHPV is available as an open-source software and can be downloaded from https://github.com/JiuxingLiang/DeepHPV.git, Contact: huzheng1998@163.com, liangjiuxing@m.scnu.edu.cn, lizheyzy@163.com.

Chemical systems biology reveals mechanisms of glucocorticoid receptor signaling.

Glucocorticoids display remarkable anti-inflammatory activity, but their use is limited by on-target adverse effects including insulin resistance and skeletal muscle atrophy. We used a chemical systems biology approach, ligand class analysis, to examine ligands designed to modulate glucocorticoid receptor activity through distinct structural mechanisms. These ligands displayed diverse activity profiles, providing the variance required to identify target genes and coregulator interactions that were highly predictive of their effects on myocyte glucose disposal and protein balance. Their anti-inflammatory effects were linked to glucose disposal but not muscle atrophy. This approach also predicted selective modulation in vivo, identifying compounds that were muscle-sparing or anabolic for protein balance and mitochondrial potential. Ligand class analysis defined the mechanistic links between the ligand-receptor interface and ligand-driven physiological outcomes, a general approach that can be applied to any ligand-regulated allosteric signaling system.

DeepEBV: a deep learning model to predict Epstein-Barr virus (EBV) integration sites.

MOTIVATION: Epstein-Barr virus (EBV) is one of the most prevalent DNA oncogenic viruses. The integration of EBV into the host genome has been reported to play an important role in cancer development. The preference of EBV integration showed strong dependence on the local genomic environment, which enables the prediction of EBV integration sites. RESULTS: An attention-based deep learning model, DeepEBV, was developed to predict EBV integration sites by learning local genomic features automatically. First, DeepEBV was trained and tested using the data from the dsVIS database. The results showed that DeepEBV with EBV integration sequences plus Repeat peaks and 2-fold data augmentation performed the best on the training dataset. Furthermore, the performance of the model was validated in an independent dataset. In addition, the motifs of DNA-binding proteins could influence the selection preference of viral insertional mutagenesis. Furthermore, the results showed that DeepEBV can predict EBV integration hotspot genes accurately. In summary, DeepEBV is a robust, accurate and explainable deep learning model, providing novel insights into EBV integration preferences and mechanisms. AVAILABILITYAND IMPLEMENTATION: DeepEBV is available as open-source software and can be downloaded from https://github.com/JiuxingLiang/DeepEBV.git. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Clinical Application of C-TIRADS Category and Contrast-Enhanced Ultrasound in Differential Diagnosis of Solid Thyroid Nodules Measuring ≥1 cm.

BACKGROUND The aim of this study was to investigate the performance of Chinese Thyroid Imaging Reporting and Data System (C-TIRADS) category combined with contrast-enhanced ultrasound (CEUS) in diagnosing thyroid cancer. MATERIAL AND METHODS From October 2020 to March 2021, 116 thyroid nodules from 113 patients who underwent conventional ultrasound and CEUS examinations at the General Hospital of Northern Theater Command were reviewed. In the conventional ultrasound examination, thyroid nodules were categorized by C-TIRADS. The nodules were reclassified based on CEUS scoring, then a combined diagnosis was made. The pathological results were taken as the criterion standard. To compare the diagnostic performance of the 3 methods according to the receiver operating characteristic curves produced for thyroid nodules. RESULTS After chi-square test, the 7 characteristics of enhancement patterns, internal homogeneity, wash-in, wash-out, ring enhancement, morphology, and contrast agent retention characteristics (CAR) were statistically different between malignant and benign tumors; A high diagnostic performance was demonstrated by C-TIRADS combined with CEUS in diagnosing thyroid cancer. The area under the curve (AUC), the sensitivity, and the specificity of C-TIRADS combined with CEUS for diagnosing thyroid cancer were 0.918 (95% CI: 0.852-0.961), 80.9% (95% CI: 69.1-89.8%), and 90.6% (95% CI: 79.3-96.9%), respectively. The AUC of C-TIRADS alone was significantly lower than that of C-TIRADS combined with CEUS (P=0.0056), while there was no significant difference between CEUS and C-TIRADS combined with CEUS (P=0.59). CONCLUSIONS The combined method of C-TIRADS and CEUS, with reduced rate of thyroid nodule biopsy and clinical application value, has higher diagnostic accuracy than the single diagnosis method.

Differential diagnosis and feature visualization for thyroid nodules using computer-aided ultrasonic diagnosis system: initial clinical assessment.

BACKGROUND: To assess the diagnostic efficacy of the computer-aided ultrasonic diagnosis system (CAD system) in differentiating benign and malignant thyroid nodules. METHODS: The images of 296 thyroid nodules were included in validation sets. The diagnostic efficacy of the CAD system was compared with that of junior physicians and senior physicians, as well as that of the combination diagnosis of the CAD system with junior physicians. The diagnostic efficacy of the CAD system for different sizes of thyroid nodules was compared. RESULTS: The diagnostic sensitivity and accuracy of the CAD system were higher than those of junior physicians (83.4% vs. 72.2%, 73.0% vs. 69.6%), but the diagnostic specificity of the CAD system was lower than that of junior physicians (62.1% vs. 66.9%). The diagnostic accuracy of the CAD system was lower than that of senior physicians (73.0% vs. 83.8%). However, the combination diagnosis of the CAD system with junior physicians had higher accuracy (81.8%) and AUC (0.842) than those of either the CAD system or junior physicians alone, and comparable diagnostic performance with those of senior physicians. The Kappa was 0.635 in the combination diagnosis of the CAD system with junior physicians, showing good consistency with the pathological results. The accuracy (76.4%) of the CAD system was the highest for nodules of 1-2 cm. CONCLUSION: The CAD system can effectively assist physicians to identify malignant and benign thyroid nodules, reduce the overdiagnosis and overtreatment of thyroid nodules, avoid unnecessary invasive fine needle aspiration, and improve the diagnostic accuracy of junior physicians.

Targeting Diagnosis of High-Risk Papillary Thyroid Carcinoma Using Ultrasound Contrast Agent With the BRAFV600E Mutation: An Experimental Study.

OBJECTIVE: High-risk papillary thyroid carcinoma (PTC) patients with BRAF mutation have lymph node and distant metastases and poor prognosis. Therefore, this study aims to develop a targeted ultrasound contrast agent for the BRAFV600E mutation to screen high-risk PTC at early stage. METHODS: The targeted lipid nanobubbles carrying BRAFV600E antibody were prepared using thin film hydration-sonication and avidin-biotin binding methods. The physicochemical properties and stability of the targeted nanobubbles were detected by transmission electron microscopy, atomic force microscopy, and confocal laser scanning microscopy. The target binding abilities of the targeted nanobubbles in the PTC cells (B-CPAP) overexpressed mutant BRAFV600E were evaluated by immunofluorescence staining, quantitative real-time polymerase chain reaction, western blot, and fluorescence microscopy. After PTC tumor models overexpressed mutant BRAFV600E were established, the enhanced images of targeted lipid nanobubbles and untargeted lipid nanobubbles on PTC tumors in nude mice were observed using contrast-enhanced ultrasound imaging. RESULTS: The targeted lipid nanobubbles revealed uniform, round morphology, and good stability with a nanoscale size. Besides, BRAFV600E monoclonal antibody was observed to be combined on the surface of lipid nanobubbles. Furthermore, the targeted nanobubbles had a good targeting diagnosis ability in PTC cells with BRAFV600E overexpression. Moreover, the targeted nanobubbles had better ultrasound enhancement and peak intensity of the time-intensity curve (P < .001) in PTC tumors with BRAFV600E overexpression as compared to the untargeted lipid nanobubbles. CONCLUSION: The targeted lipid nanobubbles carrying BRAFV600E antibody could be regarded as a potential targeted ultrasound contrast agent for the diagnosis of high-risk PTC.

Papillary thyroid carcinoma: an ultrasound-based nomogram improves the prediction of lymph node metastases in the central compartment.

OBJECTIVES: To develop a nomogram based on postoperative clinical and ultrasound findings to quantify the probability of central compartment lymph node metastases (CLNM). METHODS: A total of 952 patients with histologically confirmed papillary thyroid carcinoma (PTC) were included in this retrospective study and assigned to three groups based on sex and age. The strongest predictors for CLNM were selected according to ultrasound imaging features, and an ultrasound (US) signature was constructed. By incorporating clinical characteristics, a predictive model presented as a nomogram was developed, and its performance was assessed with respect to calibration, discrimination and clinical usefulness. RESULTS: Predictors contained in the nomogram included US signature, US-reported LN status and age. The US signature was constructed with tumour size and microcalcification. The nomogram showed excellent calibration in the training dataset, with an AUC of 0.826 (95% CI, 0.765-0.887) for male patients, 0.818 (95% CI, 0.746-0.890) for young females and 0.808 (95% CI, 0.757-0.859) for elder females. For male and young female patients, application of the nomogram to the validation cohort revealed good discrimination, with AUCs of 0.813 (95% CI, 0.722-0.904) and 0.814 (95% CI, 0.712-0.915), respectively. Conversely, for elderly female patients, the nomogram failed to show good performance with an AUC of 0.742 (95% CI, 0.661-0.823). CONCLUSION: This ultrasound-based nomogram may serve as a useful clinical tool to provide valuable information for treatment decisions, especially for male and younger female patients. KEY POINTS: • Age, gender, US-reported LN status and US signature were the strongest predictors of CLNM in PTC patients and informed the development of a predictive nomogram. • Microcalcification was the strongest predictor in the US signature, as CLMN was identified in approximately 92% of patients characterised by diffuse microcalcification. • Stratified by sex and age, this nomogram achieved good performance in predicting CLNM, especially in male and young female patients. This prediction tool may be useful as an imaging marker for identifying CLNM preoperatively in PTC patients and as a guide for personalised treatment.

Factors associated with health-related quality of life in papillary thyroid microcarcinoma patients undergoing radiofrequency ablation: a cross-sectional prevalence study.

PURPOSE: To explore the association of demographic characteristics, clinical symptoms and the fear of the disease progression factors with the physical and mental summary components of the health-related of life (HRQoL) of the papillary thyroid microcarcinoma (PTMC) patients undergoing radiofrequency ablation (RFA). METHODS: 123 PTMC survivors undergoing RFA were enrolled in this study from October 2019 to March 2020. Demographic, clinical symptoms and the fear of the disease progression data were collected. SF-36, THYCA-QoL and FoP-Q-SF were used to evaluate the HRQoL of patients, clinical symptoms and the fear of disease progression. A multivariate regression model was performed to evaluate the association between the independent variable and the HRQoL variable. RESULTS: The average self-reported HRQoL score was 81.17 ± 15.48 for the PCS and 73.40 ± 18.03 for the MCS. The multivariate linear regression model shows that the factors related to a poorer PCS were dependent for the female patients, the symptoms of neuromuscular and the throat/mouth, the fear of disease progression; the psychological disorder, symptoms of throat/mouth, inability to concentrate were related to worse scores for the MCS. The condition that was most strongly related to a poorer HRQoL (in both PCS and MCS) was the fear of their physical health. CONCLUSIONS: The factors related to significantly worse HRQoL scores across PCS and MCS for PTMC survivors include the female gender, the symptoms of neuromuscular and the throat/mouth, the psychological disorder, inability to concentrate, and the fear of their own physical health. Identification, management, and prevention of these factors are critical to improving the HRQoL of patients.

Solid benign thyroid nodules (>10 ml): a retrospective study on the efficacy and safety of sonographically guided ethanol ablation combined with radiofrequency ablation.

Background: Image-guided radiofrequency ablation (RFA) of large solid benign thyroid nodules (BTNs) usually require a high amount of energy. Injection of ethanol into a benign thyroid nodule before RFA can lower the procedural time and patient discomfort.Objective: To investigate the efficacy and safety of ethanol ablation (EA) combined with RFA in the treatment of solid BTNs (>10 ml) and to compare this modified method with RFA treatment alone.Methods: A total of 366 nodules in 366 patients were treated from June 2017 to Mar. 2018, 76 (M:F = 32:44, age 46 ± 14 years) were treated with EA + RFA and 290 (M:F = 99:191, age 49 ± 14 years) were treated with RFA. 44 patients (44 nodules) of each group formed a matched cohort after adjustment with propensity score matching. The average time, energy and power of the RFA procedure were retrospectively compared between the two groups. The postoperative nodule volume reduction ratio (VRR), compressive symptoms, cosmetic concerns, comprehensive satisfaction score, thyroid function and complications were retrospectively compared within and between the two groups after 6 months after treatment.Results: No significant differences were observed in the baseline characteristics between groups after propensity score matching adjustment. The mean RFA time (454.7 s (interquartile range (IQR), 290.8-589.0 s vs. 796.0 s (IQR, 554.0-976.30 s), p < .001), energy (3.69 ± 1.99 kJ vs. 5.10 ± 2.15 kJ, p = .009) and power (6.17 ± 1.38 W vs. 7.21 ± 1.29 W, p < .001) in the EA + RFA group were significantly lower than those in the RFA group. Mean nodule reduction at 6 months in the EA + RFA group and in the RFA group was 69.81 ± 11.48% vs. 67.43 ± 12.13% (10-30 ml, p = .454) and 62.75 ± 11.41% vs. 59.82 ± 10.53% (>30 ml, p = .456), respectively. The Medium nodules shrunk more than the large nodules (all p < .001), and the pressure symptoms and cosmetic signs significantly improved in the large nodules in both groups (all p < .05). Patients in the EA + RFA group had the highest satisfaction.Conclusions: EA combined with RFA shortened the ablation time of RFA, reduced the total energy and power required and improved patient satisfaction. This modified RFA approach may be considered a low-risk and high-efficacy alternative to treat solid BTNs greater than 10 ml in size.

Ultrasound Computer-Aided Diagnosis (CAD) Based on the Thyroid Imaging Reporting and Data System (TI-RADS) to Distinguish Benign from Malignant Thyroid Nodules and the Diagnostic Performance of Radiologists with Different Diagnostic Experience.

BACKGROUND The diagnosis of thyroid cancer and distinguishing benign from malignant thyroid nodules by junior radiologists can be challenging. This study aimed to develop a computer-aided diagnosis (CAD) system based on the Thyroid Imaging Reporting and Data System (TI-RADS) to distinguish benign from malignant thyroid nodules by analyzing ultrasound images to improve the diagnostic performance of junior radiologists. MATERIAL AND METHODS A modified TI-RADS based on a convolutional neural network (CNN) was used to develop the CAD system. This retrospective study reviewed 789 thyroid nodules from 695 patients and included radiologists with different diagnostic experience. Five study groups included the CAD group, the junior radiologist group, the intermediate-level radiologist group, the senior radiologist group, and the group in which the junior radiologist used the CAD system. The ultrasound findings were reviewed and compared with the histopathology diagnosis. RESULTS The CAD system for the diagnosis of thyroid cancer showed an accuracy of 80.35%, a sensitivity of 80.64%, a specificity of 80.13%, a positive predictive value (PPV) of 76.02%, a negative predictive value (NPV) of 84.12%, and an area under the receiver operating characteristic (ROC) curve (AUC) of 0.87. The accuracy of the junior radiologists in diagnosing thyroid cancer using CAD was similar to that of intermediate-level radiologists (79.21% vs. 77.57%; P=0.427). CONCLUSIONS The use of ultrasound CAD based on the TI-RADS showed potential for distinguishing between benign and malignant thyroid nodules and improved the diagnostic performance of junior radiologists.

[Factors Affecting Quality of Life of Patients Undergoing Radiofrequency Ablation for Papillary Thyroid Microcarcinoma].

Objective To evaluate the factors affecting health-related quality of life (HRQoL) of patients with thyroid papillary microcarcinoma (PTMC) after ultrasound-guided radiofrequency ablation (RFA).Methods The clinical data of 100 patients with PTMC who underwent reexamination after RFA in the Ultrasound Department of our center from October to December 2019 were retrospectively analyzed.Demographic information was collected.SF-36 and Thyroid Cancer-specific Health-related Quality of Life Questionnaire scales were used to assess patients' quality of life and thyroid-related specific symptoms.The SF-36 scale includes two general domains including physical component summary (PCS) and mental component summary (MCS).The impacts of demographic characteristics and thyroid-related symptoms after RFA on PCS and MCS scores were further analyzed.Results Univariate analysis and correlation analysis showed that the PCS scores in quality of life of PTMC patients were related to sex, neuromuscular, voice, concentration, sympathetic nerve, and throat/mouth complaints, psychological state, sensory symptoms, scar, chills, tingling, and headache (all P<0.1);and the MCS scores were associated with education level, residence, neuromuscular, voice, concentration, sympathetic nerve, and throat/mouth complains, psychological state, sensory symptoms, scar, chills, tingling, and headache (all P<0.1).Multivariate regression analysis showed that the PCS scores were only associated with sex and the neuromuscular and throat/mouth complains and the psychological state.The regression equation was:PCS=110.367-8.025×sex-0.213×psychological state-0.280×neuromuscular complain-0.278×throat/mouth complain.In contrast, the MCS scores were only associated with the psychological state and the throat/mouth and concentration complains, with the regression equation being:MCS=91.323-0.237×psychological state-0.437×throat/mouth-0.304×concentration.Conclusions The main risk factors affecting the quality of life of PTMC patients after ultrasound-guided RFA were female gender, psychological burden, lack of attention, and symptoms in neuromuscular system and throat/mouth.Therefore, preoperative explanations should be made according to the relevant symptoms that the patients may report, and psychological interventions should be offered after RFA to improve the quality of life of PTMC patients after treatment.

[Anhydrous Ethanol Improves Efficiency of Radiofrequency Ablation for the Treatment of Benign Thyroid Nodules:A Prospective Randomized Controlled Trial].

Objective To investigate the value of injecting a small amount of absolute ethanol into the benign solid nodules of the thyroid before radiofrequency ablation(RFA)to improve the efficiency of radiofrequency ablation. Methods A total of 98 eligible patients(98 nodules)with pathologically confirmed benign solid nodules who were treated in our center from December 2016 to February 2018 were included and randomized into ethanol ablation(EA)combined with radiofrequency ablation(RFA)group(EA+RFA group)and RFA group,with 49 patients in each group.Routine ultrasound,contrast-enhanced ultrasound(CEUS),and thyroid function test were performed before treatment and 1,3,6,and 12 months after treatment.The general information,treatment time,ablation energy,ablation power,postoperative nodule volume reduction ratio(VRR),symptom score(SS)and cosmetic score(CS),thyroid function level,and incidence of complications were compared between these two groups. Results The mean treatment time [(441.30±243.31)s vs.(790.70±349.82)s;t= 4.403, P=0.000],mean ablation energy [(3.92±2.01)kJ vs.(5.15±2.12)kJ;t=2.709, P=0.009],and mean ablation power [(6.07±1.44)W vs.(7.30±1.29)W;t=3.612, P=0.006] were significantly lower in the EA+RFA group than in the RFA group.At 3,6 and 12 months after surgery,the VRR in the EA+RFA group was(57.73±11.07)%(t=-3.16, P<0.001),(64.40±10.56)%(t=-5.45, P<0.001),and(77.29±8.48)%(t=-10.46, P<0.001),respectively;the VRR in the RFA group was(55.44±13.01)%(t=-1.76, P<0.001),(65.28±11.33)%(t=-5.09, P<0.001),and(75.17±9.84)%(t=-8.93, P<0.001),which were significantly smaller than those before surgery.There was no significant difference in VRR between the EA+RFA group and the RFA group at 1(t=3.41, P=0.33),3(t=2.05, P=0.21),6(t=2.77, P=0.49),and 12 months(t=5.05, P=0.10)after treatment.During the follow-up,no recurrence of nodules was observed on CEUS.In the EA+RFA group,the SS [(1.77±0.86)vs.(5.54±2.15);t=9.63, P<0.001] and the CS[(1.39±0.77)vs.(3.32±0.61);t=10.09, P=0.004]at 12 months after surgery were significantly lower than those before surgery.In the RFA group,SS [(1.63±1.04)vs.(5.90±1.79);t=12.72, P<0.001] and CS [(1.64±0.83)vs.(3.15±0.72);t=8.13, P=0.012] at 12 months after surgery were also significantly lower than those before surgery.The CSS in the EA+RFA group was significantly lower than that in the RFA group [(0.93±0.55)vs.(2.44±0.53);t=-11.70, P=0.007].Both groups had no significant change in thyroid function during the follow-up period,and no serious complications were observed. Conclusion Anhydrous alcohol injection can effectively improve the efficiency of radiofrequency ablation in treating benign solid thyroid nodules and is effective in reducing nodule volume,alleviating compressive symptoms,and decreasing cosmetic discomfort.

[Quantitative Evaluation of Sciatic Nerve Crush Injury with Conventional Ultrasound Combined with Shear-wave Elastography in Rabbit Models].

Objective To explore the value of conventional ultrasound combined with shear-wave elastography in the quantitative evaluation of sciatic nerve crush injury in rabbit models. Methods Forty healthy male New Zealand white rabbits were randomly divided into four groups (n=10 in each group):three crush injury (CI) groups (2,4,and 8 weeks after crush) and control group (without injury). The thickness and stiffness of the crushed sciatic nerves and denervated triceps surae muscles were measured at different time points and compared with histopathologic parameters. Inter-reader variability was assessed with intraclass correlation coefficients. Results Compared with the control group,the inner diameters of the sciatic nerves significantly increased in the 2-week CI group [(1.65±0.34) mm vs. (0.97±0.15) mm,P=0.00] but recovered to the nearly normal level in the 8-week CI group [(1.12±0.18) mm vs. (0.97±0.15) mm,P=0.06];however,compared with control group [(8.75±1.02)kPa],the elastic modulus of the nerves increased significantly in all the CI groups [2-week:(14.77±2.53) kPa;4-week:(19.12±3.46) kPa;and 8-week:(28.39±5.26) kPa;all P=0.00];pathologically,massive hyperplasia of collagen fibers were found in the nerve tissues. The thickness of denervated triceps surae muscle decreased gradually,and the elastic modulus decreased 2 weeks after injury but increased gradually in the following 6 weeks;pathologically,massive hyperplasia of collagen fibers and adipocytes infiltration were visible,along with decreased muscle wet-weight ratio and muscle fiber cross-sectional area. The inter-reader agreements were good. Conclusion Conventional ultrasound combined with shear-wave elastography is feasible for the quantitative evaluation of the morphological and mechanical properties of crushed nerves and denervated muscles.

Risk stratification of cervical lesions using capture sequencing and machine learning method based on HPV and human integrated genomic profiles.

From initial human papillomavirus (HPV) infection and precursor stages, the development of cervical cancer takes decades. High-sensitivity HPV DNA testing is currently recommended as primary screening method for cervical cancer, whereas better triage methodologies are encouraged to provide accurate risk management for HPV-positive women. Given that virus-driven genomic variation accumulates during cervical carcinogenesis, we designed a 39 Mb custom capture panel targeting 17 HPV types and 522 mutant genes related to cervical cancer. Using capture-based next-generation sequencing, HPV integration status, somatic mutation and copy number variation were analyzed on 34 paired samples, including 10 cases of HPV infection (HPV+), 10 cases of cervical intraepithelial neoplasia (CIN) grade and 14 cases of CIN2+ (CIN2: n = 1; CIN2-3: n = 3; CIN3: n = 9; squamous cell carcinoma: n = 1). Finally, the machine learning algorithm (Random Forest) was applied to build the risk stratification model for cervical precursor lesions based on CIN2+ enriched biomarkers. Generally, HPV integration events (11 in HPV+, 25 in CIN1 and 56 in CIN2+), non-synonymous mutations (2 in CIN1, 12 in CIN2+) and copy number variations (19.1 in HPV+, 29.4 in CIN1 and 127 in CIN2+) increased from HPV+ to CIN2+. Interestingly, 'common' deletion of mitochondrial chromosome was significantly observed in CIN2+ (P = 0.009). Together, CIN2+ enriched biomarkers, classified as HPV information, mutation, amplification, deletion and mitochondrial change, successfully predicted CIN2+ with average accuracy probability score of 0.814, and amplification and deletion ranked as the most important features. Our custom capture sequencing combined with machine learning method effectively stratified the risk of cervical lesions and provided valuable integrated triage strategies.

Inhibition of microRNA-132 attenuates inflammatory response and detrusor fibrosis in rats with interstitial cystitis via the JAK-STAT signaling pathway.

Interstitial cystitis (IC) is a heterogeneous syndrome with unknown etiology, and microRNAs (miRs) were found to be involved in IC. In our study, we aim to explore the role of miR-132 in the inflammatory response and detrusor fibrosis in IC through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway in rat models. A rat model of IC was established and treated with the miR-132 mimic, miR-132 inhibitor, and/or JAK-STAT signaling pathway inhibitor AG490. Enzyme-linked immunosorbent assay was applied to measure the expression of interleukin (IL)-6, IL-10, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1). The urodynamic test was performed to assess urodynamic parameters, and reverse transcription quantitative polymerase chain reaction and Western blot analysis for the expression of miR-132, STAT4, suppressors of cytokine signaling 3 (SOCS3), JAK2, vascular endothelial growth factor (VEGF), IFN-γ, and TNF-α. IC rats treated with miR-132 inhibitor and AG490 had decreased collagen fiber, inflammatory cell infiltration, and mast cells, lower expression of IL-6, IL-10, IFN-γ, TNF-α, ICAM-1, collagens I and III, and alleviated urodynamic parameters and decreased expression of STAT4, VEGF, JAK2, IFN-γ, TNF-α, and increased expression of SOCS3. Taken together, our data indicate that downregulation of miR-132 alleviates inflammatory response and detrusor fibrosis in IC via the inhibition of the JAK-STAT signaling pathway.

Impaired decision-making and functional neuronal network activity in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with cognitive deficit but the exact neural mechanisms remain unclear. PURPOSE: To explore sequential brain activities using functional magnetic resonance imaging (fMRI) during the performance of a decision-making task, and to determine whether serum or clinical markers can reflect the involvement of the brain in SLE. SUBJECTS: Sixteen female SLE patients without overt clinical neuropsychiatric symptoms and 16 healthy controls were included. FIELD STRENGTH/SEQUENCE: 1.5T, T1 -weighted anatomic images, gradient-echo echo-planar imaging sequence, and 3D images. ASSESSMENT: The computer-based Iowa Gambling Task (IGT) for assessing decision-making was performed by SLE patients and 16 matched controls; brain activity was recorded via blood oxygen level-dependent (BOLD) fMRI. The amplitudes of the average BOLD responses were calculated for each individual subject, and activation data from fMRI experiments were compared between the two groups. STATISTICAL TESTS: Two-sample t-test; repeated-measures analysis of variance (ANOVA); linear regression analyses. RESULTS: Imaging revealed activity in a distributed network of brain regions in both groups, including the ventromedial prefrontal cortex (vmPFC), the orbitofrontal cortex (OFC), the dorsolateral prefrontal cortex (dlPFC), the anterior cingulate cortex (ACC), the posterior cingulate cortex (PCC), and the striatum, as well as the insular, parietal, and occipital cortices. Compared to controls, SLE patients showed lower activation in a convergence zone and the limbic system, namely, the OFC, vmPFC, ACC, and PCC, but greater activation in memory, emotion, and behavior systems involving the dlPFC, the insular cortex and the striatum. Furthermore, brain activation in the vmPFC was positively correlated with IGT scores (r = 0.63, P < 0.001), but inversely related to disease activity (r = -0.57, P < 0.01). DATA CONCLUSION: The dynamics among the aforementioned neural systems (some hyperfunctioning, others hypofunctioning) may shed some light on the pathologic mechanisms underlying SLE without overt clinical neuropsychiatric symptoms. In addition, disease activity may potentially be used as an effective biomarker reflecting cerebral involvement in SLE. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;48:1508-1517.

Synthesis of novel steroidal agonists, partial agonists, and antagonists for the glucocorticoid receptor.

Adverse effects of glucocorticoids could be limited by developing new compounds that selectively modulate anti-inflammatory activity of the glucocorticoid receptor (GR). We have synthesized a novel series of steroidal GR ligands, including potent agonists, partial agonists and antagonists with a wide range of effects on inhibiting secretion of interleukin-6. Some of these new ligands were designed to directly impact conformational stability of helix-12, in the GR ligand-binding domain (LBD). These compounds modulated GR activity and glucocorticoid-induced gene expression in a manner that was inversely correlated to the degree of inflammatory response. In contrast, compounds designed to directly modulate LBD epitopes outside helix-12, led to dissociated levels of GR-mediated gene expression and inflammatory response. Therefore, these new series of compounds and their derivatives will be useful to dissect the ligand-dependent features of GR signaling specificity.