RNA-Seq Reveals Protective Mechanisms of Mongolian Medicine Molor-Dabos-4 on Acute Indomethacin-Induced Gastric Ulcers in Rats.

This study aimed to apply transcriptomics to determine how Molor-Dabos-4 (MD-4) protects healthy rats against indomethacin (IND)-induced gastric ulcers and to identify the mechanism behind this protective effect. Rats were pretreated with MD-4 (0.3, 1.5, or 3 g/kg per day) for 21 days before inducing gastric ulcers by oral administration with indomethacin (30 mg/kg). Unulcerated and untreated healthy rats were used as controls. Effects of the treatment were assessed based on the ulcer index, histological and pathological examinations, and indicators of inflammation, which were determined by enzyme-linked immunosorbent assay. Transcriptomic analysis was performed for identifying potential pharmacological mechanisms. Eventually, after identifying potential target genes, the latter were validated by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). After pretreatment with MD-4, gastric ulcers, along with other histopathological features, were reduced. MD-4 significantly (p < 0.05) increased the superoxide dismutase (SOD) levels in ulcers and reduced pepsin, TNF-α, and IL-6 levels. RNA-seq analysis identified a number of target genes on which MD-4 could potentially act. Many of these genes were involved in pathways that were linked to anti-inflammatory and antioxidant responses, and other protective mechanisms for the gastric mucosa. qRT-PCR showed that altered expression of the selected genes, such as Srm, Ryr-1, Eno3, Prkag3, and Eef1a2, was consistent with the transcriptome results. MD-4 exerts protective effects against IND-induced gastric ulcers by reducing inflammatory cytokines and pepsin and increasing the expression of SOD levels. Downregulation of Srm, Ryr-1, Eno3, Prkag3, and Eef1a2 genes involved in regulating arginine and proline metabolism, calcium signaling pathway, HIF-1 signaling pathway, oxytocin signaling pathway, and legionellosis are possibly involved in MD-4-mediated protection against gastric ulcers.

Usefulness of Noncontrast MRI-Based Radiomics Combined Clinic Biomarkers in Stratification of Liver Fibrosis.

Purpose: To develop and validate a radiomic nomogram based on texture features from out-of-phase T1W images and clinical biomarkers in prediction of liver fibrosis. Materials and Methods: Patients clinically diagnosed with chronic liver fibrosis who underwent liver biopsy and noncontrast MRI were enrolled. All patients were assigned to the nonsignificant fibrosis group with fibrosis stage <2 and the significant fibrosis group with stage ≥2. Texture parameters were extracted from out-of-phase T1-weighted (T1W) images and calculated using the Artificial Intelligent Kit (AK). Boruta and LASSO regressions were used for feature selection and a multivariable logistic regression was used for construction of a combinational model integrating radiomics and clinical biomarkers. The performance of the models was assessed by using the receiver operator curve (ROC) and decision curve. Results: ROC analysis of the radiomics model that included the most discriminative features showed AUCs of the training and test groups were 0.80 and 0.78. A combinational model integrating RADscore and fibrosis 4 index was established. ROC analysis of the training and test groups showed good to excellent performance with AUC of 0.93 and 0.86. Decision curves showed the combinational model added more net benefit than radiomic and clinical models alone. Conclusions: The study presents a combinational model that incorporates RADscore and clinical biomarkers, which is promising in classification of liver fibrosis.

A rare case of duodenal spindle cell lipoma with gastrointestinal bleeding.

The manuscript reports a rare case of duodenal spindle cell lipoma (SCL), which is a rarely reported benign lipomatous neoplasm of the gastrointestinal tract. It is less commonly observed within the duodenum. Our patient presented with gastrointestinal bleeding, which is a rare symptom of lipomas. This report describes the appearance of the neoplasm on endoscopy as well as endoscopic ultrasonography. The ulcer on the surface of the neoplasm is another rare feature. The correct diagnosis of SCL was based on its microscopic features and immunohistochemical findings. We believe that our study makes a significant contribution to the literature because this information will be of practical use to clinicians for the management of similar conditions and encourage other researchers to validate our findings.

Use of Texture Analysis on Noncontrast MRI in Classification of Early Stage of Liver Fibrosis.

Purpose. To compare the diagnostic value of texture analysis- (TA-) derived parameters from out-of-phase T1W, in-phase T1W, and T2W images in the classification of the early stage of liver fibrosis. Methods. Patients clinically diagnosed with hepatitis B infection, who underwent liver biopsy and noncontrast MRI scans, were enrolled. TA parameters were extracted from out-of-phase T1-weighted (T1W), in-phase T1W, and T2-weighted (T2W) images and calculated using Artificial Intelligent Kit (AK). Features were extracted including first-order, shape, gray-level cooccurrence matrix, gray-level run-length matrix, neighboring gray one tone difference matrix, and gray-level differential matrix. After statistical analyses, final diagnostic models were constructed. Receiver operating curves (ROCs) and areas under the ROC (AUCs) were used to assess the diagnostic value of each final model and 100-time repeated cross-validation was applied to assess the stability of the logistic regression models. Results. A total of 57 patients were enrolled in this study, with 27 in the fibrosis stage < 2 and 30 in stages ≥ 2. Overall, 851 features were extracted per ROI. Eight features with high correlation were selected by the maximum relevance method in each sequence, and all had a good diagnostic performance. ROC analysis of the final models showed that all sequences had a preferable performance with AUCs of 0.87, 0.90, and 0.96 in T2W and in-phase and out-of-phase T1W, respectively. Cross-validation results reported the following values of mean accuracy, specificity, and sensitivity: 0.98 each for out-of-phase T1W; 0.90, 0.89, and 0.90 for in-phase T1W; and 0.86, 0.88, 0.84 for T2W in the training set, and 0.76, 0.81, and 0.72 for out-of-phase T1W; 0.74, 0.72, and 0.75 for in-phase T1W; and 0.63, 0.64, and 0.63 for T2W for the test group, respectively. Conclusion. Noncontrast MRI scans with texture analysis are viable for classifying the early stages of liver fibrosis, exhibiting excellent diagnostic performance.

Clinical Study of the Prediction of Malignancy in Thyroid Nodules: Modified Score versus 2017 American College of Radiology's Thyroid Imaging Reporting and Data System Ultrasound Lexicon.

The clinical importance of thyroid nodules rests with the need to exclude thyroid cancer. In the present study, we developed a modified Thyroid Imaging Reporting and Data System (TI-RADS) score using gray-scale ultrasound, contrast-enhanced ultrasound (CEUS) and shear-wave elastography (SWE) images to predict malignancy of thyroid nodules and compared this modified score system with the subjective scoring criteria based on the Thyroid Imaging Reporting and Data System (TI-RADS, 2017 edition). The results revealed that by using SWE and CEUS (enhanced pattern) to downgrade TI-RADS category 4 and 5 nodules, the malignancy rate for TI-RADS category 4 and 5 nodules increased from 47.6% with American College of Radiology (ACR) TI-RADS assessment alone to 49.4% with ACR TI-RADS combined with shear wave elastography (SWE) and CEUS (enhanced pattern). Likewise, by using the modified TI-RADS to adjust TI-RADS category 3 nodules, the malignancy rate for TI-RADS category 3 nodules increased from 13.9%-20.0%. The discriminating power for detection of malignancy of the variable score 2 (ACR TI-RADS + SWE + CEUS), with an area under the curve (AUC) of 0.899 (95% confidence interval [CI]: 86.1%-93.6%), was higher than that of score 1 (ACR TI-RADS), with an AUC of 0.862 (95% CI: 81.9%-90.6%; p > 0.05). With a point 4.5 as the optimal cutoff value, a score of 1 predicted malignancy with an accuracy of 75.6%, sensitivity of 85.0% and specificity of 71.6%. However, with a point 5.5 as the optimal cutoff value, a score of 2 predicted malignancy with an accuracy of 84.9%, sensitivity of 81.0% and specificity of 86.6%. The modified TI-RADS based on ACR TI-RADS + SWE + CEUS (enhanced pattern) could contribute to a reduction in the number of biopsies performed on benign nodules and the implementation of consistent follow-up in clinical practice.

Depletion of H3K79 methyltransferase Dot1L promotes cell invasion and cancer stem-like cell property in ovarian cancer.

DOT1-like protein (Dot1L) is the sole methyltransferase for methylation of lysine 79 in histone H3. Dot1L-dependent H3K79 methylation is involved in many biological processes, including telomeric silencing, cell cycle regulation, transcriptional activation and DNA repair. Genome-wide sequencing studies have revealed recurrent deletion and mutations of Dot1L gene in many types of human malignancies including ovarian cancer, however the role of Dot1L in ovarian cancer are largely unknown. To demonstrate the role of Dot1L in ovarian cancer, the expression of Dot1L was knocked out in ovarian cancer cells using CRISPR/Cas9 technology in the present study. Dot1L loss showed minimal effect on cell growth, but significantly promoted cell invasion and induced cancer stem-like cell property in ovarian cancer cells. Mechanistically, loss of Dot1L downregulated the expression of tight junction makers E-Cadherin and TJP1 and upregulated the expression of ALDH1A1 through Wnt signaling activation. Our data indicate potential tumor suppressor function of Dot1L in ovarian cancer, which is correlated with observed deletion of Dot1L gene in ovarian cancer patients, further study is granted to elucidate the function of Dot1L in tumorigenesis and progression in ovarian cancer.

A potential biomarker hsa-miR-200a-5p distinguishing between benign thyroid tumors with papillary hyperplasia and papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most common endocrine cancer with a significantly increase of the incidence recently. Several cytokines, such as thyroid peroxidase (TPO), cluster of differentiation 56 (CD56), Galectin-3, mesothelial cell (MC), cytokeratin 19 (CK19) and BRAF (B-raf) were recommended to be tested by immunohistochemistry (IHC) for a definitive diagnosis, but were still limited in clinical use because of their relative lower sensitivity and specificity. MicroRNA (miRNA), as a new molecular biomarkers, however, has not been reported yet so far. To address this, hsa-miR-200a-5p, a miRNA, was selected and detected in PTC patients by in situ hybrization with benign thyroid tumor with papillary hyperplasia as a control, and the differential expression of hsa-miR-200a-5p between fresh PTC tissues and control was detected by qRT-PCR. Expressive levels of cytokines of TPO, CD56, Galectin-3, MC, CK19 and B-raf were also detected by immunohistochemistry. The correlation was analyzed by SPSS software using Spearman methods. As expected, the hsa-miR-200a-5p expressive level was significantly increased in PTC patients, compared to that of control, and was consistent with that of TPO, CD56, Galectin-3, MC, CK19 and B-raf. In addition, expression of hsa-miR-200a-5p showed negative correlation to that of TPO (rs = - 0.734; **: P < 0.01) and CD56 (rs = - 0.570; **: P < 0.01), but positive correlation to that of Galectin-3 (rs = 0.601; **: P < 0.01), MC (rs = 0.508; **: P < 0.01), CK19 (rs = 0.712; **: P < 0.01) and B-raf (rs = 0.378; **: P < 0.01). PTC and papillary benign thyroid papillary hyperplasia are difficult to distinguish in morphology, so requiring immunohistochemistry to further differentiate the diagnosis, however, for the existing clinical common diagnostic marker for immunohistochemistry, the sensitivity and accuracy are low, it is easy to miss diagnosis. Therefore, there is an urgent need for a rapid and sensitive molecular marker. So miR-200a-5p can be used to assist in the diagnosis of PTC at the molecular level, and as a biomarker, can be effectively used to distinguish between PTC and benign thyroid tumor with papillary hyperplasia.

Absorption enhancement of adefovir dipivoxil by incorporating MCT and ethyl oleate complex oil phase in emulsion.

AIM: To improve the oral absorption of adefovir dipivoxil (ADV) by employing MCT and the esterase inhibitor ethyl oleate (EO) as a complex oil phase in emulsion. METHODS: EO was used as the esterase inhibitor, and its inhibitory effect on esterase activity was assessed in rat intestinal homogenates. ADV emulsions with or without EO were prepared. The emulsions' protective effect against intestinal metabolism was evaluated in rat luminal contents, ex vivo, as well as in vivo. RESULTS: The IC(50) of EO in intestinal mucosal homogenates was 2.2 mg/mL. The emulsions exhibited significant protective effects in rat luminal contents compared to a simple suspension (98.7%, 96.3%, 95.7% vs 74.7%, P<0.01). The permeability calculated from the emulsion containing EO was significantly different (11.4 x 10(-6) vs 7.4/8.0 x 10(-6), P<0.05) from the simple suspension or the emulsion without EO in an ex vivo assay. A bioavailability study in vivo revealed that emulsions containing both EO and MCT as a complex oil phase demonstrated 1.6- and 1.5-fold enhancements in area under the curve (AUC(0-12)) values (5358 vs 3386/3618, P<0.05), respectively, when compared with emulsions containing EO or MCT as a single oil phase. CONCLUSION: Heterotic lipid formulations (emulsions) with an esterase inhibitor (ie, EO) may be useful in protecting ester prodrugs from intestinal metabolism and increasing their oral bioavailability.