Design, synthesis, and evaluation of novel quindoline derivatives with fork-shaped side chains as RNA G-quadruplex stabilizers for repressing oncogene NRAS translation.

NRAS mutation is the second most common oncogenic factor in cutaneous melanoma. Inhibiting NRAS translation by stabilizing the G-quadruplex (G4) structure with small molecules seems to be a potential strategy for cancer therapy due to the NRAS protein's lack of a druggable pocket. To enhance the effects of previously reported G4 stabilizers quindoline derivatives, we designed and synthesized a novel series of quindoline derivatives with fork-shaped side chains by introducing (alkylamino)alkoxy side chains. Panels of experimental results showed that introducing a fork-shaped (alkylamino)alkoxy side chain could enhance the stabilizing abilities of the ligands against NRAS RNA G-quadruplexes and their anti-melanoma activities. One of them, 10b, exhibited good antitumor activity in the NRAS-mutant melanoma xenograft mouse model, showing the therapeutic potential of this kind of compounds.

Diagnostic performance of endorectal ultrasound combined with shear wave elastography for rectal tumors staging.

OBJECTIVE: This study aims to analyze the performance of endorectal ultrasound (ERUS) combined with shear wave elastography (SWE) for rectal tumor staging. METHODS: Forty patients with rectal tumors who had surgery were enrolled. They underwent ERUS and SWE examinations before surgery. Pathological results were used as the gold standard for tumor staging. The stiffness values of the rectal tumor, peritumoral fat, distal normal intestinal wall, and distal perirectal fat were analyzed. The diagnostic accuracy of ERUS stage, tumor SWE stage, ERUS combined with tumor SWE stage, and ERUS combined with peritumoral fat SWE stage were compared and evaluated by receiver operating characteristic (ROC) curve to select the best staging index. RESULTS: From T1 to T3 stage, the maximum elasticity (Emax) of the rectal tumor increased gradually (p < 0.05). The cut-off values of adenoma/T1 and T2, T2 and T3 tumors were 36.75 and 85.15kPa, respectively. The diagnostic coincidence rate of tumor SWE stage was higher than that of ERUS stage. Overall diagnostic accuracy of ERUS combined with peritumoral fat SWE Emax restaging was significantly higher than that of ERUS. CONCLUSIONS: ERUS combined with peritumoral fat SWE Emax for tumor restaging can effectively distinguish between stage T2 and T3 rectal tumors, which provides an effective imaging basis for clinical decisions.

Design, synthesis, and evaluation of 9-(pyrimidin-2-yl)-9H-carbazole derivatives disrupting mitochondrial homeostasis in human lung adenocarcinoma.

Since more than 85% of lung cancer cases are non-small cell lung cancer (NSCLC), finding novel agents with anti-tumor activities is meaningful for NSCLC patients. Mitochondria is essential for cellular energy metabolism in cancer, and regulating mitochondrial bioenergetics is emerging as a practical approach for cancer treatment and prevention. The carbazole scaffold is an active structure showing anti-cancer biological activity, and the structural diversity has been expanded through the improvement and optimization of synthesizing methods. To find novel carbazole derivatives with great anti-tumor potential and explore structures variety, we designed and synthesized a series of 9-(pyrimidin-2-yl)-9H-carbazole derivatives based on the previously reported Cp∗Rh(III)/H+ tandem catalytic system. With thoroughly bioactivity exploration, we found benzo[d] [1,3]dioxol-5-yl(9-(pyrimidin-2-yl)-9H-carbazol-1-yl)methanone (compound 5n) showed notable activity in disrupting the mitochondrial homeostasis, induced cell cycle arrest and apoptosis in human adenocarcinoma cells, and finally showed anti-tumor activity in an NSCLC-xenograft mice model.

Strain Imaging in the Evaluation of Thyroid Nodules: The Associated Factors Leading to Misdiagnosis.

This study analyzed which imaging characteristics may contribute to misdiagnosis of benign and malignant thyroid nodules (TNs) through strain imaging (SI). We analyzed SI parameters and conventional ultrasound (CUS) characteristics of 264 nodules with histopathology results and we applied binary logistic regression analysis to select independent variables for incorrect SI results. The elastography imaging (EI) score and the virtual touch tissue imaging (VTI) score of malignant TNs were remarkably higher than that in benign TNs. VTI, of which the false-positive rate (FPR), the false-negative rate (FNR), and the cutoff value were 47.6% (39/82), 17.6% (32/182) and 3.5, presented higher diagnostic performance than EI. Aspect ratio (odd ratio [OR]: 14.208) and intra-nodular calcification (OR: 20.384) were significantly associated with false-positive VTI findings, while posterior acoustic feature (OR: 30.424) was significantly associated with false-negative VTI findings. Sex (OR: 0.221) and aspect ratio (OR: 0.268) were negatively associated with false-negative EI findings. In conclusion, sex and aspect ratio significantly affect the accuracy of EI results, while aspect ratio, intra-nodular calcification and posterior acoustic features notably affect the accuracy of VTI results. These CUS features of TNs should not be ignored before explaining SI examination results.

Abnormal Brain Glucose Metabolism in Papillary Thyroid Cancer Patients 4 Weeks After Withdrawal of Levothyroxine: A Cross-Sectional Study Using 18F-FDG PET/CT.

Background: There is no doubt that thyroid dysfunction is associated with psychiatric disorders. A large amount of thyroid carcinoma patients displayed mood disorders after the withdrawal of levothyroxine (LT4). However, it is unclear whether the disorders are related to the transient withdrawal of LT4, and if yes, what the possible underlying mechanism is. This study aims to investigate the abnormal regional cerebral glucose metabolism (rCMRglu) in a group of papillary thyroid cancer (PTC) patients without LT4 for 4 weeks and prove the relationship between the abnormal rCMRglu with depression and anxiety. Methods: Brain 18F-FDG PET/CT data of 38 consecutive PTC patients with high/intermediate-risk from June 2016 to December 2017 have been analyzed. Of the 38 patients, 23 are in the LT4 withdrawal group (WG) and 15 in the LT4 replacement group (RG). These patients were also evaluated for depressive and anxiety symptoms within 24 h after the scans based on the Hamilton Depression Rating Scale (17 items, HRDS-17) and the Hamilton Anxiety Rating Scale (HAMA) respectively. Results: Thirty-eight patients (12 men, 26 women; age range, 25-69 years; mean age, 45.8 years) were selected in the study. Compared with the RG, patients in WG showed depression and anxiety with higher total scores of HRDS-17 and HAMA (14.7 ± 5.8 vs 3.8 ± 5.5, t = -5.74, p = 0.00; 9.3 ± 4.3 vs 2.7 ± 4.1, t = -4.74, p = 0.00, respectively). In the brain glucose metabolism analysis, the WG patients showed lower rCMRglu in Occipital_Mid_R and Postcentral_L. On the other hand, data illustrated significant rCMRglu increases in the Frontal_Sup_Orb_L. Compared with the healthy group (HG), the rCMRglu of the Postcentral_L and Precuneus_L showed hypoactivity, but the Hippocampus_R and the Temporal_Inf_L showed hyperactivity. This analysis yielded a significant correlation between abnormal rCMRglu with the free thyroxine level, the serum thyroid-stimulating hormone level, HRDS-17, and HAMA scores. Conclusions: The findings showed that more PTC patients exhibited depression and anxiety after LT4 withdrawal for 4 weeks. More attention should be paid to these hypothyroid patients while they were in the hospital. Such a short-term LT4 withdrawal also likely induced abnormal rCMRglu. Our study attempts to explain the possible mechanism of mood disorders related to transient hypothyroidism.

Evaluation of thyroid nodules with coexistent Hashimoto's thyroiditis according to various ultrasound-based risk stratification systems：A retrospective research.

PURPOSES: To investigate the efficiency of Thyroid Imaging Reporting and Data System (TI-RADS) proposed by KWAK, the American College of Radiology, and the 2015 American Thyroid Association (ATA) guidelines for thyroid nodules with Hashimoto's thyroiditis (HT) and to determine whether HT influence the diagnostic performance of these risk-stratification systems. METHODS: A total of 101 nodules with HT and 101 nodules with non-HT were retrospectively analyzed by ultrasound-based diagnostic classifications and compared with histopathological results. The areas under the receiver operating characteristic curve (AUCs) were calculated for comparative analysis. RESULTS: In the HT group, KWAK TI-RADS has the best sensitivity (91.67%), while ACR TI-RADS has the highest specificity (82.93%) and accuracy (81.19%). The AUCs of ACR TI-RADS, ATA guidelines, and KWAK TI-RADS were 0.844, 0.782, and 0.830, respectively. In the non-HT group, the sensitivity and specificity of three risk-stratification systems had no significant difference. The AUCs of ACR TI-RADS, ATA guidelines, and KWAK TI-RADS were 0.872, 0.839, and 0.874, respectively. No significant difference was found in diagnostic effectiveness of the same systems with both contexts. CONCLUSIONS: ACR TI-RADS performed the most effective for thyroid nodules in HT, whereas KWAK TI-RADS was the best for those in non-HT. Both of TI-RADS (ACR and KWAK) provided higher diagnostic effectiveness than ATA guidelines in HT or in non-HT. Moreover, HT could not affect the diagnostic performance of these risk-stratification systems.

Comparison of Supersonic Shear Wave Imaging-Derived Renal Parenchyma Stiffness Between Diabetes Mellitus Patients With and Without Diabetic Kidney Disease.

This study aims to evaluate the difference in renal parenchyma stiffness assessed by measuring Young's modulus (YM) using a supersonic shear wave imaging (SSI) technique among healthy patients and patients with type 2 diabetes mellitus (DM) with and without diabetic kidney disease (DKD). We analyzed the correlations of YM with clinical information and conventional ultrasound parameters. All patients (N = 124) were divided into three groups: (i) healthy patients (patients without kidney disease or type 2 DM, N = 31); (ii) patients with type 2 DM without kidney disease (N = 38); and (iii) patients with DKD (N = 55). Conventional and SSI ultrasound examinations were performed in all individuals for both kidneys. Then, we recorded renal length, width, parenchyma thickness, interlobar arterial resistive index (RI) and values of mean, mininum and maximum YM. The mean values of these parameters for the left and right kidneys were calculated for statistical analysis. Statistical significance was considered at p < 0.05. Among all ultrasound parameters, the mean YM demonstrated the largest area under the receiver operating characteristic (ROC) curve (0.860). The areas under the ROC curve (AUCs) for renal length, width, parenchyma thickness, interlobar arterial RI, minimum YM and maximum YM were 0.493, 0.616, 0.507, 0.733, 0.848 and 0.794, respectively. The corresponding cutoff value of mean YM was 31.73 kPa, with a sensitivity of 85.5% and a specificity of 71.0%. The mean YM in patients with type 2 DM without kidney disease (31.44 ± 3.83 kPa) was significantly higher than that in the healthy group (26.45 ± 4.32 kPa) and lower than that in the DKD group (37.60 ± 6.56 kPa). Patients with type 2 DM without kidney disease were considered as stage 0 of DKD. Thus, the mean YM in the control group was significantly lower than that in the stage 0, 2, 3, 4 and 5 subgroups. The mean YM in the stage 0-2 subgroups was lower than that in the stage 5 group, and the mean YM in the stage 0 group was lower than that in the stage 4 group. In the DKD group, the mean YM had a positive correlation with cystine-c (r = 0.634), urea (r = 0.596), creatine (r = 0.690), uric acid (r = 0.263), albumin/creatinine ratio (r = 0.428) and the presence or absence of diabetic retinopathy (r = 0.354). The mean YM also had a negative correlation with the estimated glomerular filtration rate (r = -0.657). SSI is a non-invasive method with which to diagnose DKD and has a performance superior to that of conventional ultrasound. In addition, SSI may provide a secondary index for the staging of DKD and the monitoring of renal damage in type 2 DM patients.

Virtual touch tissue imaging and quantification (VTIQ) in the evaluation of breast lesions: The associated factors leading to misdiagnosis.

PURPOSE: To investigate the factors that could cause a misdiagnosis in virtual touch tissue imaging and quantification (VTIQ) when differentiating benign and malignant breast lesions, and to analyze the imaging characteristics of those lesions with incorrect findings. METHODS: The conventional ultrasound (CUS) features and the VTIQ parameters of 153 benign lesions and 99 malignant lesions were retrospectively analyzed and compared with histopathological and/or core-needle biopsy (CNB)-proven results. Independent variables that led to inaccurate VTIQ results were selected by binary logistic regression analysis. RESULTS: The maximum shear wave speed (SWS-max), the mean SWS (SWS-mean), the minimum SWS (SWS-min), the lesion-to-fat SWS ratio (SWS-L/F), and the lesion-to-gland SWS ratio (SWS-L/G) in malignant lesions were significantly higher than those in benign lesions (all P < 0.001). The false-positive rate (FPR) of benign lesions and the false-negative rate (FNR) of malignant lesions were 9.8% and 19.2%, respectively, using an SWS-max cut-off value of 4.46 m/s. Diameter, depth, and posterior acoustic features were independent variables related to false-positive VTIQ findings (P: 0.049, 0.010 and 0.032, respectively). The invasive status and the histologic grade of infiltrating carcinoma were significantly associated with false-negative VTIQ findings (P: 0.026 and 0.015). CONCLUSION: Diameter, depth, posterior acoustic features, invasive status, and histologic grade have a significant influence on the accuracy of VTIQ results, and these characteristics of breast lesions should be taken into account when interpreting the results of VTIQ examinations.

Pre-operative Conventional Ultrasound and Sonoelastography Evaluation for Predicting Axillary Lymph Node Metastasis in Patients with Malignant Breast Lesions.

The objective of our study was to evaluate the association between the sonoelastography features of breast tumor and axillary lymph node metastasis (ALNM) in patients with breast cancer. In a cohort of 106 women with breast cancer, the conventional ultrasound features and elasticity parameters by elasticity imaging and Virtual Touch Tissue Imaging & Quantification (VTIQ) were retrospectively analyzed. Ultrasound and elastography findings were compared with pathologic axillary lymph node status. Receiver operating characteristic curve analysis was used to evaluate diagnostic performance. Pathologically, the overall incidence of ALNM was 39.6% (42/106) in the final analysis. ALNM was significantly more frequent in tumors with elasticity imaging scores >4.5, maximal shear wave velocity values (Smax) >6.42 m/s and mean shear wave velocity values (Smean) >5.66 m/s, respectively. The sensitivity, specificity and accuracy were 78.6%, 54.7% and 64.2% for elasticity imaging score; 85.7%, 54.7% and 67.0% for Smax; and 59.5%, 79.7% and 71.7% for Smean, respectively Elastography features, including elasticity imaging score and VTIQ, can be used to supplement conventional ultrasound to predict ALNM in patients with breast cancers.

Comparison of strain and acoustic radiation force impulse elastography of breast lesions by qualitative evaluation.

OBJECTIVES: To compare the diagnostic performance of conventional strain elastography (CSE) and acoustic radiation force impulse (ARFI) induced SE for qualitative assessment of breast lesions and evaluate the additional value of the two techniques combined with Breast Imaging Reporting and Data System (BI-RADS) respectively for the differentiation of benign and malignant breast lesions. METHODS: In a cohort of 110 women, the conventional ultrasound (US) features and the elasticity scores of CSE and ARFI induced SE were recorded. The diagnostic performances of BI-RADS, elastography and BI-RADS plus elastography were evaluated, including the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity and accuracy. RESULTS: Pathologically, there were forty-eight malignant and sixty-two benign breast lesions in the final analysis. The AUCs for CSE and ARFI induced SE are similar (CSE, 0.807; ARFI induced SE, 0.846; p > 0.05), however, the specificity of the latter method was significantly higher than that of CSE (83.9% vs. 58.1%, p = 0.004) in differentiating breast lesions. The accuracy and specificity of BI-RADS plus ARFI induced SE (84.5%, 80.6%, respectively) were significantly higher than BI-RADS alone (73.6%, 54.8%, respectively) and BI-RADS plus conventional SE (72.7%, 56.5%, respectively), respectively (p < 0.05) without loss of sensitivity. CONCLUSIONS: Our study showed that BI-RADS plus ARFI induced SE had a better diagnostic performance in the diagnosis of breast lesions in comparison with BI-RADS alone or BI-RADS plus CSE.

Initial experience of automated breast volume scanning (ABVS) and ultrasound elastography in predicting breast cancer subtypes and staging.

OBJECTIVES: Breast cancer is a heterogeneous disease consisting of distinct histopathological subtypes with different clinical outcomes. In this article, we identified the automated breast volume scanning (ABVS) and shear wave velocity (SWV) characteristics of different pathological types of breast carcinoma. METHODS: A retrospective review of both ABVS and SWV imaging of 118 consecutive breast masses was performed. The imaging features of both techniques were assessed with reference to histopathological results. RESULTS: Echo heterogeneity with a smooth and lobulated margin was a significant feature more frequently found in mucinous carcinoma groups (100%, P < 0.05). Between different stages of ductal carcinoma, echo homogeneity was more likely in high-grade ductal carcinomas (P < 0.05). SWV differences existed between inside tumor areas and either tumor boundary or tissues outside the tumors (P < 0.05), and values differed between different breast carcinoma stages. The central and tumor margin areas of ductal carcinomas were much harder than in tubular carcinoma and micro-carcinoma, respectively (P < 0.05). SWV ROC curve analyses yielded a cut-off value of 3.015 m/s between ductal carcinoma in situ (DCIS) and invasive ductal carcinoma in the central part of lesions, with 83.5% sensitivity and 80% specificity for T0 vs T1-3 staging. CONCLUSIONS: Since some features were associated with different breast carcinoma types and stages, ABVS and SWV imaging has the potential to give clues about breast carcinoma differentiation in a non-invasive manner.

Improving N(6)-methyladenosine site prediction with heuristic selection of nucleotide physical-chemical properties.

N(6)-methyladenosine (m(6)A) is one of the most common and abundant post-transcriptional RNA modifications found in viruses and most eukaryotes. m(6)A plays an essential role in many vital biological processes to regulate gene expression. Because of its widespread distribution across the genomes, the identification of m(6)A sites from RNA sequences is of significant importance for better understanding the regulatory mechanism of m(6)A. Although progress has been achieved in m(6)A site prediction, challenges remain. This article aims to further improve the performance of m(6)A site prediction by introducing a new heuristic nucleotide physical-chemical property selection (HPCS) algorithm. The proposed HPCS algorithm can effectively extract an optimized subset of nucleotide physical-chemical properties under the prescribed feature representation for encoding an RNA sequence into a feature vector. We demonstrate the efficacy of the proposed HPCS algorithm under different feature representations, including pseudo dinucleotide composition (PseDNC), auto-covariance (AC), and cross-covariance (CC). Based on the proposed HPCS algorithm, we implemented an m(6)A site predictor, called M6A-HPCS, which is freely available at http://csbio.njust.edu.cn/bioinf/M6A-HPCS. Experimental results over rigorous jackknife tests on benchmark datasets demonstrated that the proposed M6A-HPCS achieves higher success rates and outperforms existing state-of-the-art sequence-based m(6)A site predictors.

The application of Virtual Touch tissue quantification (VTQ) in diagnosis of thyroid lesions: a preliminary study.

OBJECTIVES: Virtual Touch tissue quantification (VTQ) is a quantified ultrasound (US) acoustic radiation force impulse (ARFI) imaging method that provides numerical measurements (wave-velocity values) of tissue stiffness. The purpose of this study was to detect whether VTQ could be applied to differentiate between benign and malignant thyroid lesions. METHODS: Healthy subjects' thyroid tissue and thyroid lesions were examined by VTQ to analyze their elasticity after conventional ultrasound. All the thyroid lesions were analyzed pathologically after surgery and correlated the VTQ values with the pathological results. RESULTS: The VTQ value of healthy thyroid tissue, the benign lesions, and the malignant lesions were 1.69 ± 0.41 m/s, 2.03 ± 0.42 m/s, and 3.10 ± 1.08 m/s, respectively. The VTQ value of the malignant lesions was higher than that of the healthy thyroid tissue and the benign lesions (both p<0.001). The VTQ value of the benign lesions was higher than that of the healthy thyroid tissue (p<0.001). With a cutoff value of 2.42 m/s, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for differentiating between the benign and the malignancy lesions were 80.00%, 89.23%, 87.05%, 69.56%, and 93.54%, respectively. CONCLUSIONS: VTQ could provide quantitative elasticity measurements, which might play an important role in differentiating between benign and malignant thyroid lesions.

The role of fascin in migration and invasion of urothelial carcinoma of the bladder.

INTRODUCTION: To investigate the roles of fascin in migration and invasiveness in bladder urothelial carcinoma. MATERIALS AND METHODS: Immunohistochemical detection of fascin in urothelial carcinoma samples and inhibition the expression of fascin in the urothelial carcinoma cell line were performed, then the differences in cell behaviors before and after silencing of the fascin gene were tested. RESULTS: In our study, we found that overexpression of fascin was more frequent in urothelial carcinoma tissues (p < 0.001). Fascin expression was positively correlated with histological grade (p = 0.024) and pT stage (p < 0.001). After transfection of fascin shRNA, the expressions of fascin in 5637 cells and BIU87 cells were efficiently decreased according to real-time RT-PCR and Western blot analysis. When fascin was inhibited, a significant decrease in migration and invasion, and increase in adhesion were observed in 5637 cells and BIU87 cells. However, there was no significant change in the proliferation of 5637 cells or BIU87 cells with or without inhibition of the fascin gene. CONCLUSIONS: Fascin expression can be used as a predictor for transformation and progression of urothelial carcinoma, and reduction of fascin levels may represent a novel therapeutic strategy for urothelial carcinoma of the bladder.