A Porphyrin-Based 3D Metal-Organic Framework Featuring [Cu8Cl6]10+ Cluster Secondary Building Units: Synthesis, Structure Elucidation, Anion Exchange, and Peroxidase-Like Activity.

Herein, we report a rare example of cationic three-dimensional (3D) metal-organic framework (MOF) of [Cu5Cl3(TMPP)]Cl5 ⋅ xSol (denoted as Cu-TMPP; H2TMPP=meso-tetrakis (6-methylpyridin-3-yl) porphyrin; xSol=encapsulated solvates) supported by [Cu8Cl6]10+ cluster secondary building units (SBUs) wherein the eight faces of the Cl--based octahedron are capped by eight Cu2+. Surface-area analysis indicated that Cu-TMPP features a mesoporous structure and its solvate-like Cl- counterions can be exchanged by BF4 -, PF6 -, and NO3 -. The polyvinylpyrrolidone (PVP) coated Cu-TMPP (denoted as Cu-TMPP-PVP) demonstrated good ROS generating ability, producing ⋅OH in the absence of light (peroxidase-like activity) and 1O2 on light irradiation (650 nm; 25 mW cm-2). This work highlights the potential of Cu-TMPP as a functional carrier of anionic guests such as drugs, for the combination therapy of cancer and other diseases.

Computational analysis of PD-L1 dimerization mechanism induced by small molecules and potential dynamical properties.

The design of small molecule inhibitors that target the programmed death ligand-1 (PD-L1) is a forefront issue in immune checkpoint blocking therapy. Small-molecule inhibitors have been shown to exert therapeutic effects by inducing dimerization of the PD-L1 protein, however, the specific mechanisms underlying this dimerization process remain largely unexplored. Furthermore, there is a notable lack of comparative studies examining the binding modes of structurally diverse inhibitors. In view of the research gaps, this work employed molecular dynamics simulations to meticulously examine the interactions between two distinct types of inhibitors and PD-L1 in both monomeric and dimeric forms, and predicted the dimerization mechanism. The results revealed that inhibitors initially bind to a PD-L1 monomer, subsequently attracting another monomer to form a dimer. Notably, symmetric inhibitors observed superior binding efficiency compared to other inhibitors. Key residues, including Ile54, Tyr56, Met115 and Tyr123 played a leading role in binding. Structurally, symmetric inhibitors were capable of thoroughly engaging the binding pocket, promoting a more symmetrical formation of PD-L1 dimers. Furthermore, symmetric inhibitors formed more extensive hydrophobic interactions with protein residues. The insights garnered from this research are expected to significantly contribute to the rational design and optimization of small molecule inhibitors targeting PD-L1.

Explore the pharmacological basis of ShengJiYiSui decoction in the treatment of amyotrophic lateral sclerosis based on network pharmacology and molecular docking technology.

Neurodegenerative illnesses have long been handled clinically by traditional Chinese medicine. This study is the first time to explore the pharmacological basis of application in amyotrophic lateral sclerosis (ALS) through network pharmacology and molecular docking techniques. In the present investigation, the TCMSP database and HIT2 database were examined for 9 TCM constituents of Sheng Ji Yu Sui Decoction (SJYSD), and the desired sites for the components were searched in the Drugbank database. and the Sjysd-target network was constructed. Associated targets for Amyotrophic lateral sclerosis (ALS) were then retrieved and collected in the OMIM, TTD, Genecards and DisGeNET databases. Protein-protein interaction and enrichment analysis were performed for the common targets of drugs and diseases, and molecular anchoring for the chosen core targets and related molecules was carried out. The results showed that SJYSD had 100 active compounds corresponding to 598 targets. ALS has a total of 5,325 genes. SJYSD and ALS share 163 genes, and these targets involve PI3K-AKT signaling, p53 signaling and IL-17 signaling, etc. The core components of luteolin and quercetin were discovered and may be used to treat ALS by regulating PI3K-AKT signaling pathway by HSP90AB1 protein.

Lead exposure induces neuronal apoptosis via NFκB p65/RBBP4/Survivin signaling pathway.

Lead (Pb), as a heavy metal that is easily exposed in daily life, can cause damage to various systems of body. Apoptosis is an autonomous cell death process regulated by genes in order to maintain the stability of internal environment, which plays an important role in the development of nervous system. RB binding protein 4 (RBBP4) is one of the core histone binding subunits and is closely related to the apoptosis process of nervous system cells. However, it is not known whether RBBP4 can regulate neuronal apoptosis in lead-exposed environments. We exposed PC12 cells to 0 µM (control group), 1 µM, and 100 µM PbAc for 24 h to obtain cell samples. The female rats ingested drinking water containing 0, 0.5 g/L, and 2.0 g/L PbAc from the first day of pregnancy to three weeks after delivery to obtain hippocampal tissue samples from mammary rats. The results of TUNEL showed that lead exposure promoted the onset of apoptosis in cells and hippocampus. The mRNA and protein levels of the apoptosis-related protein Survivin were significantly reduced in the lead-exposed group compared to the control group. In addition, we found that lead exposure reduces the mRNA and protein levels of RBBP4 in PC12 cells and hippocampus, and increases the mRNA and protein levels of NFκB p65. Moreover, inhibiting NFκB p65 can reverse the decrease in RBBP4 expression in the lead exposure model. Overexpression of RBBP4 increased Survivin expression and reduced apoptosis induced by lead exposure. This suggests that lead exposure induces apoptosis through the NFκB p65/RBBP4/Survivin signaling pathway.

Comprehensive analysis unveils altered binding kinetics of 5-/6-methylCytosine/adenine modifications in R2R3-DNA system.

Recent studies have shown that DNA methylation is an important epigenetic marker. Two prominent forms are methylation of the C5 position of cytosine and methylation of the C6 position of adenine. Given the vital significance of DNA methylation, investigating the mechanisms that influence protein binding remains a compelling pursuit. This study used molecular dynamics simulations to investigate the binding patterns of R2R3 protein and four differentially methylated DNAs. The alanine scanning combined with interaction entropy method was used to identify key residues that respond to different methylation patterns. The order of protein binding ability to DNA is as follows: unmethylated DNA > A11 methylation (5'-A6mAC-3') (6m2A system) > A10 methylation (5'-6mAAC-3') (6m1A system) > both A10 and A11 methylation (5'-6mA6mAC-3') (6mAA system) > C12 methylation (5'-AA5mC-3') (5mC system). All methylation systems lead to the sixth α helix (H6) (residues D105 to L116) moving away from the binding interface, and in the 5mC and 6m1A systems, the third α helix (H3) (residues G54 to L65) exhibits a similar trend. When the positively charged amino acids in H3 and H6 move away from the binding interface, their electrostatic and van der Waals interactions with the negatively charged DNA are weakened. Structural changes induced by methylation contributed to the destabilization of the hydrogen bond network near the original binding site, except for the 6m2A system. Moreover, there is a positive correlation between the number of methylated sites and the probability of distorting the DNA structure. Our study explores how different methylation patterns affect binding and structural adaptability, and have implications for drug discovery and understanding diseases related to abnormal methylation.

[Determination of seven monoaromatic hydrocarbon metabolites by ultra performance liquid chromatography-tandem mass spectrometry].

Monoaromatic hydrocarbons (MAHs) such as benzene, toluene, and xylene are important anthropogenic pollutants in the urban atmosphere. The detection of urinary MAH metabolites are included in human biomonitoring programs in several countries, including Canada, the United States, Italy, and Germany, because their evaluation is vital to monitor the exposure of humans to MAHs. To this end, herein, a method was developed for the determination of seven MAH metabolites through ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). An aliquot of 0.5 mL urine was fortified with an isotopic labeled internal standard solution before being hydrolyzed by 40 µL of 6 mol/L HCl solution, followed by extraction using a 96-well EVOLUTE®EXPRESS ABN solid-phase extraction plate. The samples were washed with 1.0 mL of methanol-water (10∶90, v/v) and eluted with 1.0 mL methanol. The eluate was diluted four times with water prior to use in instrumental analysis. Chromatographic separation was achieved using an ACQUITY UPLC HSS T3 column (100 mm×2.1 mm, 1.8 µm), with gradient elution using 0.1% formic acid as mobile phase A and methanol as mobile phase B. The detection of seven analytes was performed using a triple-quadrupole mass spectrometer equipped with a negative electrospray ionization source in the multiple reaction monitoring mode. The linear ranges of the seven analytes varied from 0.1-20 µg/L to 2.5-500 mg/L, with correlation coefficients greater than 0.995. The method detection limits were 1.5, 0.02, 0.1, 900, 0.6, and 4 µg/L for trans,trans-muconic acid (MU), S-phenylmercapturic acid (PMA), S-benzylmercapturic acid (BMA), hippuric acid (HA), 2-methyl hippuric acid (2MHA), and 3-methyl hippuric acid (3MHA)+4-methyl hippuric acid (4MHA), respectively. The limits of quantification were 5, 0.05, 0.4, 3000, 2, and 12 µg/L for MU, PMA, BMA, HA, 2MHA, and 3MHA+4MHA, respectively. The method was verified by spiking urine samples at three different concentration levels, with recovery rates ranging from 84% to 123%. The intra- and inter-day precisions were 1.8%-8.6% and 1.9%-21.4%, respectively. The extraction efficiencies were 68%-99%, and the matrix effects ranged from -11% to -87%. The urine samples obtained from the German external quality assessment scheme (round 65) were used to assess the accuracy of this method. Both high and low concentrations of MU, PMA, HA, and methyl hippuric acid were within the tolerance range. All analytes in the urine samples were found to be stable for up to seven days at room temperature (20 ℃, absence of light), with less than 15% change in concentration. Analytes in urine samples were found to be stable for at least 42 d at 4 ℃ and -20 ℃, or for six freeze-thaw cycles and up to 72 h in an autosampler (8 ℃). The method was applied to the analysis of 16 non-smokers' and 16 smokers' urine samples. The detection rates of MU, BMA, HA, and 2MHA were 100% in both non-smokers' and smokers' urine samples. PMA was detected in 75% non-smokers' and 100% smokers' urine samples. 3MHA+4MHA was detected in 81% non-smokers' urine and in all smokers' urine samples. Statistical differences were found for MU, PMA, 2MHA, and 3MHA+4MHA between the two groups (p<0.001). The established method has good robustness and can provide reliable results. The experiments were carried out in a high-throughput manner with large sample sizes, owing to the small sample volume, and allowed the successful detection of the seven MAH metabolites in human urine.

Long-term outcomes of arthroscopic synovectomy and core decompression through multiple small bone holes for early-stage avascular necrosis of the femoral head.

OBJECTIVE: This study described a minimally invasive approach for the management of early-stage avascular necrosis of the femoral head, which integrated arthroscopic intra-articular decompression and core decompression by drilling multiple small holes. METHOD: A total of 126 patients with 185 hip avascular necrosis were included between March 2005 and January 2008, and the hips were classified, based on the Association Research Circulation Osseous staging system, into stage I (n = 43), stage II (n = 114), and stage III (n = 28). Arthroscopic intra-articular inspection and debridement, along with drilling of multiple small holes for core decompression, were performed. The Modified Harris hip score system and radiographs were used to assess the pre- and post-surgery outcomes. RESULTS: One hundred and three patients (involving 153 hips) were followed up successfully for an average of 10.7 ± 3.4 years (range: 9-12 years). After surgery, the overall survival rate was 51.6% (79 hips), and the clinical survival rates were 79%, 72%, 52%, 32%, and 10% for patients with stage I, IIa, IIb, IIc, and III, respectively. The outcomes of patients with Association Research Circulation Osseous Stages I or IIA were better than those of other stages, while hips with a large necrotic area had poor results. This approach preserved the original biomechanical strength of the femoral head after core decompression and eliminated arthritis factors in the hip joint. CONCLUSION: The core decompression with multiple small-size holes is an effective method for treating early-stage avascular necrosis of the femoral head, particularly in those with pathological changes in the hip joint. LEVEL OF EVIDENCE: Therapeutic study, Level IV.

A New Arthroscopic Tightrope Suture-Button Fixation Procedure for Tibial Eminence Avulsion Fracture.

This case-series outcome study presents a new arthroscopic technique for tibial eminence avulsion fracture (TEAF) with double-tunnel using two tightrope suture buttons. From May 2017 to July 2020, we performed a new arthroscopic technique for TEAF with double tunnels, using two tightrope suture buttons on 13 patients. Clinical assessments included anterior drawer, Lachman, and pivot shift tests, the International Knee Documentation Committee (IKDC), Lysholm knee scores, visual analog scale (VAS) scores, and range of motion (ROM). An independent observer noted conditions before surgery and during the last follow-up. The patients had an average follow-up of 26.2 months, ranging from 15 to 37 months. During the last postsurgical follow-up, the anterior drawer, Lachman, and pivot shift tests were negative in all the cases. According to the IKDC, Lysholm, and VAS final scores, all patients presented a significant knee function improvement at last follow-ups compared with preoperatively. The study shows that satisfactory results about an anatomic reduction of the fragment, knee stability, function, and strength can be achieved with the new arthroscopic technique for TEAF with double tunnels using two tightrope suture buttons. This study is a therapeutic case series and its level of evidence is IV.

Molecular investigation of the dual inhibition mechanism for targeted P53 regulator MDM2/MDMX inhibitors.

Inhibitors that competitively bind MDM2/MDMX can block the inhibition of P53 by MDM2/MDMX and restart its tumor-suppressive effect. Molecular studies targeting MDM2/MDMX inhibitors have always been a hot topic in anticancer drug design. Although numerous inhibitors have been designed previously against MDM2/MDMX, their dual inhibition efficacy has not been demonstrated, and few studies assessed the general causes affecting the dual inhibition of MDM2/MDMX by these inhibitors. Here, molecular dynamics simulations and alanine scanning combined with the interaction entropy method were employed to precisely investigate whether 16 inhibitors could dually inhibit MDM2/MDMX and the similarities and differences in the interaction modes. Thereby addressing the key residue sites affecting dual inhibition. Residues L54/M53, I61/60, M62/61, Y67/66, and V93/92 of MDM2/MDMX, which are in corresponding positions in both protein structures, provide significant conditions for these inhibitors to bind to MDM2/MDMX tightly. In addition, most of these inhibitors prefer to bind MDM2 than MDMX, and residues H96 and I99 in MDM2 are attractive targets for inhibitors, resulting in inhibitors binding to MDM2/MDMX with different affinity. These key residues should be considered in the development of dual inhibitors. For these 16 inhibitors, most have dual inhibitory potential for MDM2/MDMX based on the binding affinity of the complexes. Still, it is questionable whether they can exert excellent dual inhibition considering the assessment of the hot-spots. At least their binding affinity for MDMX is not superior to that for MDM2 due to the difference in energy of the van der Waals interactions at the key sites. Furthermore, based on the analysis of three representative inhibitors (TUZ/HRH and HRQ with different binding preferences for MDM2/MDMX), 3-chloropyridine in TUZ leads to the differential binding affinity between the inhibitor and MDM2/MDMX. It readily forms hydrophobic interactions with the surrounding residues H96 and I99. But this phenomenon does not occur in the TUZ-MDMX system, implying the critical role of residues H96/P95 and I99/L98. And the completely different binding mechanism of HRQ binding to MDM2/MDMX explains its inability to inhibit MDM2 well. Thus, we are cautious about its dual inhibitory ability. Besides, HRH is more prone to strong van der Waals interactions with MDM2 than MDMX whereas its 2-chlorofluorobenzene is detrimental to this. We hope that these findings will provide reliable molecular insights for the screening and optimization of targeting MDM2/MDMX dual inhibitors.

Case Report: Torsade de Pointes Induced by the Third-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Osimertinib Combined With Litsea Cubeba.

Torsades de Pointes (TdP) occurred in a 68-year-old female with epidermal growth factor receptor (EGFR) mutant lung cancer administered osimertinib, the third-generation EGFR tyrosine kinase inhibitor (TKI). Electrocardiogram (ECG) recorded at Tdp showed QT prolongation (QTc = 515 ms), to which a Traditional Chinese Medicine (TCM) named "Litsea Cubeba" may have contributed. After discontinuation of osimertinib and Litsea Cubeba, magnesium supplementation, potassium supplementation, lidocaine infusion, and the pacemaker frequency adjustment, Tdp terminated. However, QT prolongation sustained at discharge (QTc = 528 ms), partly because of the emergency use of amiodarone. Osimertinib may prolong the QT interval leading to TdP, especially when multiple risk factors to lengthen QT interval are incidentally overlapped. Thus, regular monitoring of ECG and appropriate management of concomitant drugs are highly recommended.

The correlation study on chest CT features and kidney injury in severe COVID-19 pneumonia from a multicenter cohort study.

Background: Among confirmed severe COVID-19 patients, although the serum creatinine level is normal, they also have developed kidney injury. Early detection of kidney injury can guide doctors to choose drugs reasonably. Study found that COVID-19 have some special chest CT features. The study aimed to explore which chest CT features are more likely appear in severe COVID-19 and the relationship between related (special) chest CT features and kidney injury or clinical prognosis. Methods: In this retrospective study, 162 patients of severe COVID-19 from 13 medical centers in China were enrolled and divided into three groups according to the estimated glomerular filtration rate (eGFR) level: Group A (eGFR < 60 ml/min/1.73 m2), Group B (60 ml/min/1.73 m2 ≤ eGFR < 90 ml/min/1.73 m2), and Group C (eGFR ≥ 90 ml/min/1.73 m2). The demographics, clinical features, auxiliary examination, and clinical prognosis were collected and compared. The chest CT features and eGFR were assessed using univariate and multivariate Cox regression. The influence of chest CT features on eGFR and clinical prognosis were calculated using the Cox proportional hazards regression model. Results: Demographic and clinical features showed significant differences in age, hypertension, and fatigue among the Group A, Group B, and Group C (all P < 0.05). Auxiliary examination results revealed that leukocyte count, platelet count, C-reactive protein, aspartate aminotransferase, creatine kinase, respiratory rate ≥ 30 breaths/min, and CT images rapid progression (>50%) within 24-48 h among the three groups were significantly different (all P < 0.05). Compared to Group C (all P < 0.017), Groups A and B were more likely to show crazy-paving pattern. Logistic regression analysis indicated that eGFR was an independent risk factor of the appearance of crazy-paving pattern. The eGFR and crazy-paving pattern have a mutually reinforcing relationship, and eGFR (HR = 0.549, 95% CI = 0.331-0.909, P = 0.020) and crazy-paving pattern (HR = 2.996, 95% CI = 1.010-8.714, P = 0.048) were independent risk factors of mortality. The mortality of severe COVID-19 with the appearance of crazy-paving pattern on chest CT was significantly higher than that of the patients without its appearance (all P < 0.05). Conclusions: The crazy-paving pattern is more likely to appear in the chest CT of patients with severe COVID-19. In severe COVID-19, the appearance of the crazy-paving pattern on chest CT indicates the occurrence of kidney injury and proneness to death. The crazy-paving pattern can be used by doctors as an early warning indicator and a guidance of reasonable drug selection.

Diagnostic Performance of Diffusion Kurtosis Imaging for Benign and Malignant Breast Lesions: A Systematic Review and Meta-Analysis.

Purpose: Magnetic resonance imaging (MRI) has a high sensitivity for differentiating between malignant and non-malignant breast lesions but is sometimes limited due to its low specificity. Here, we performed a meta-analysis to evaluate the diagnostic performance of mean kurtosis (MK) and mean diffusivity (MD) values in magnetic resonance diffusion kurtosis imaging (DKI) for benign and malignant breast lesions. Methods: Original articles on relevant topics, published from 2010 to 2019, in PubMed, EMBASE, and WanFang databases were systematically reviewed. According to the purpose of the study and the characteristics of DKI reported, the diagnostic performances of MK and MD were evaluated, and meta-regression was conducted to explore the source of heterogeneity. Results: Fourteen studies involving 1,099 (451 benign and 648 malignant) lesions were analyzed. The pooled sensitivity, pooled specificity, positive likelihood ratio, and negative likelihood ratio for MD were 0.84 (95% confidence interval (CI), 0.81-0.87), 0.83 (95% CI, 0.79-0.86), 4.44 (95% CI, 3.54-5.57), and 0.18 (95% CI, 0.13-0.26), while those for MK were 0.89 (95% CI, 0.86-0.91), 0.86 (95% CI, 0.82-0.89), 5.72 (95% CI, 4.26-7.69), and 0.13 (95% CI, 0.09-0.19), respectively. The overall area under the curve (AUC) was 0.91 for MD and 0.95 for MK. Conclusions: Analysis of the data from 14 studies showed that MK had a higher pooled sensitivity, pooled specificity, and diagnostic performance for differentiating between breast lesions, compared with MD.

Diagnosis of Cardiac Amyloidosis Using a Radiomics Approach Applied to Late Gadolinium-Enhanced Cardiac Magnetic Resonance Images: A Retrospective, Multicohort, Diagnostic Study.

Objectives: To assess the potential of a radiomics approach of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) in the diagnosis of cardiac amyloidosis (CA). Materials and Methods: This retrospective study included 200 patients with biopsy-proven light-chain (AL) amyloidosis. CA was diagnosed on the basis of systemic amyloidosis confirmed with evidence of cardiac involvement by imaging and clinical biomarkers. A total of 139 patients [54 ± 8 years, 75 (54%) men] in our institution were divided into training cohort [n = 97, mean age of 53 ± 8 years, 54 (56%) men] and internal validation cohort [n = 42, mean age: 56 ± 8 years, 21 (50%) men] with a ratio of 7:3, while 61 patients [mean age: 60 ± 9 years, 42 (69%) men] from the other two institutions were enrolled for external validation. Radiomics features were extracted from global (all short-axis images from base-to-apex) left ventricular (LV) myocardium and three different segments (basal, midventricular, and apex) on short-axis LGE images using the phase-sensitive reconstruction (PSIR) sequence. The Boruta algorithm was used to select the radiomics features. This model was built using the XGBoost algorithm. The two readers performed qualitative and semiquantitative assessment of the LGE images based on the visual LGE patterns, while the quantitative assessment was measured using a dedicated semi-automatic CMR software. The diagnostic performance of the radiomics and other qualitative and quantitative parameters were compared by a receiver operating characteristic (ROC) curve analysis. A correlation between radiomics and the degree of myocardial involvement by amyloidosis was tested. Results: A total of 1,906 radiomics features were extracted for each LV section. No statistical significance was indicated between any two slices for diagnosing CA, and the highest area under the curve (AUC) was found in basal section {0.92 [95% confidence interval (CI), 0.86-0.97] in the LGE images in the training set, 0.89 (95% CI, 0.79-1.00) in the internal validation set, and 0.92 (95% CI, 0.85-0.99) in the external validation set}, which was superior to the visual assessment and quantitative LGE parameters. Moderate correlations between global or basal radiomics scores (Rad-scores) and Mayo stage in all patients were reported (Spearman's Rho = 0.61, 0.62; all p < 0.01). Conclusion: A radiomics analysis of the LGE images provides incremental information compared with the visual assessment and quantitative parameters on CMR to diagnose CA. Radiomics was moderately correlated with the severity of CA. Further studies are needed to assess the prognostic significance of radiomics in patients with CA.

rh-ES and Chemotherapy in Advanced Gastrointestinal Cancer in China: A Meta-analysis.

BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of recombinant human endostatin (rh-ES) combined with chemotherapy in advanced gastrointestinal tumors in China. METHODS: A literature search was performed in PubMed, Medline, Springer, Elsevier Science Direct, Weipu, Wanfang, and China National Knowledge Infrastructure (CNKI), with the last report through September 2019. The included research was scored using a modified Jadad scale, and a meta-analysis was performed using RevMan 5.3 software. RESULTS: Twenty articles including 905 participants (experimental group [rh-ES combined with chemotherapy] 459; control group [chemotherapy alone] 446) were considered. The total effective rate for the experimental group in advanced gastrointestinal tumors was higher than that of the control group (P<0.05). No significant difference in adverse reactions was seen between the two groups (P>0.05). CONCLUSIONS: The short-term efficacy of rh-ES combined with chemotherapy for advanced gastrointestinal tumors was better, with fewer adverse reactions.

Acute Angle of Multilobulated Contours Improves the Risk Classification of Thymomas.

Background: Computed tomography plays an important role in the identification and characterization of thymomas. It has been mainly used during preoperative evaluation for clinical staging. However, the reliable prediction of histological risk types of thymomas based on CT imaging features requires further study. In this study, we developed and validated a nomogram based on CT imaging and included new indices for individualized preoperative prediction of the risk classification of thymomas. Methods: We conducted a retrospective, multicenter study that included 229 patients from two Chinese medical centers. All the patients underwent cross-sectional CT imaging within 2 weeks before surgery. The results of pathological assessments were retrieved from existing reports of the excised lesions. The tumor perimeter that contacted the lung (TPCL) was evaluated and a new quantitative indicator, the acute angle (AA) formed by adjacent lobulations, was measured. Two predictive models of risk classification were created using the least absolute shrinkage and selection operator (LASSO) method in a training cohort for features selection. The model with a smaller Akaike information criterion was then used to create an individualized imaging nomogram, which we evaluated regarding its prediction ability and clinical utility. Results: A new CT imaging-based model incorporating AA was developed and validated, which had improved predictive performance during risk classification of thymomas when compared with a model using traditional imaging predictors. The new imaging nomogram with AA demonstrated its clinical utility by decision curve analysis. Conclusions: Acute angle can improve the performance of a CT-based predictive model during the preoperative risk classification of thymomas and should be considered a new imaging marker for the evaluation and treatment of patients with thymomas. On the contrary, TPCL is not useful as a predictor for the risk classification of thymomas in this study.

MR-Based Radiomics for Differential Diagnosis between Cystic Pituitary Adenoma and Rathke Cleft Cyst.

BACKGROUND: It is often tricky to differentiate cystic pituitary adenoma from Rathke cleft cyst with visual inspection because of similar MRI presentations between them. We aimed to design an MR-based radiomics model for improving differential diagnosis between them. METHODS: Conventional diagnostic MRI data (T1-,T2-, and postcontrast T1-weighted MR images) were obtained from 215 pathologically confirmed patients (105 cases with cystic pituitary adenoma and the other 110 cases with Rathke cleft cyst) and were divided into training (n = 172) and test sets (n = 43). MRI radiomics features were extracted from the imaging data, and semantic imaging features (n = 15) were visually estimated by two radiologists. Four classifiers were used to construct radiomics models through 5-fold crossvalidation after feature selection with least absolute shrinkage and selection operator. An integrated model by combining radiomics and semantic features was further constructed. The diagnostic performance was validated in the test set. Receiver operating characteristic curve was used to evaluate and compare the performance of the models at the background of diagnostic performance by radiologist. RESULTS: In test set, the combined radiomics and semantic model using ANN classifier obtained the best classification performance with an AUC of 0.848 (95% CI: 0.750-0.946), accuracy of 76.7% (95% CI: 64.1-89.4%), sensitivity of 73.9% (95% CI: 56.0-91.9%), and specificity of 80.0% (95% CI: 62.5-97.5%) and performed better than multiparametric model (AUC = 0.792, 95% CI: 0.674-0.910) or semantic model (AUC = 0.823, 95% CI: 0.705-0.941). The two radiologists had an accuracy of 69.8% and 74.4%, respectively, sensitivity of 69.6% and 73.9%, and specificity of 70.0% and 75.0%. CONCLUSIONS: The MR-based radiomics model had technical feasibility and good diagnostic performance in the differential diagnosis between cystic pituitary adenoma and Rathke cleft cyst.

Inhibition mechanism and hot-spot prediction of nine potential drugs for SARS-CoV-2 Mpro by large-scale molecular dynamic simulations combined with accurate binding free energy calculations.

Coronavirus disease 2019 (COVID-19), which is caused by a new coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading around the world. However, a universally effective treatment regimen has not been developed to date. The main protease (Mpro), a key enzyme of SARS-CoV-2, plays a crucial role in the replication and transcription of this virus in cells and has become the ideal target for rational antiviral drug design. In this study, we performed molecular dynamics simulations three times for these complexes of Mpro (monomeric and dimeric) and nine potential drugs that have a certain effect on the treatment of COVID-19 to explore their binding mechanism. In addition, a total of 12 methods for calculating binding free energy were employed to determine the optimal drug. Ritonavir, Arbidol, and Chloroquine consistently showed an outstanding binding ability to monomeric Mpro under various methods. Ritonavir, Arbidol, and Saquinavir presented the best performance when binding to a dimer, which was independent of the protonated state of Hie41 (protonated at Nε) and Hid41 (protonated at Nδ), and these findings suggest that Chloroquine may not effectively inhibit the activity of dimeric Mproin vivo. Furthermore, three common hot-spot residues of Met165, Hie41, and Gln189 of monomeric Mpro systems dominated the binding of Ritonavir, Arbidol, and Chloroquine. In dimeric Mpro, Gln189, Met165, and Met49 contributed significantly to binding with Ritonavir, Arbidol, and Saquinavir; therefore, Gln189 and Met165 might serve as the focus in the discovery and development of anti-COVID-19 drugs. In addition, the van der Waals interaction played a significant role in the binding process, and the benzene ring of the drugs showed an apparent inhibitory effect on the normal function of Mpro. The binding cavity had great flexibility to accommodate these different drugs. The results would be notably helpful for enabling a detailed understanding of the binding mechanisms for these important drug-Mpro interactions and provide valuable guidance for the design of potent inhibitors.

[Systematic evaluation and sequential Meta-analysis of modified Xuefu Zhuyu Decoction combined with Western medicine in treatment of leiomyoma].

CNKI, PubMed and other databases were retrieved to extract eligible randomized controlled trial(RCT) about modified Xuefu Zhuyu Decoction(MXZD) combined with Western medicine(trial group) versus Western medicine alone(control group) in the treatment of leiomyoma. Therefore, a total of 25 RCTs were included, involving 2 328 patients. Bias risk evaluation tool in Cochrane Handbook 5.1.0 was used for evaluating the quality of these RCTs. Meta-analysis was performed for the reported indicators, including total efficiency, serum hormone level [progesterone(P), luteinizing hormone(LH), estradiol(E_2), follicle stimulating hormone(FSH)], uterine size, fibroids size and adverse reactions by using Stata 14.0 software. Meta-analysis showed that the total efficiency(RR=1.21,95%CI[1.17,1.25],P<0.05) of trial group was better than that of control group. Serum hormone level(WMD_P=-3.86,95%CI[-4.31,-3.41],P<0.05; WMD_(LH)=-3.64,95%CI[-4.47,-2.82],P<0.05; WMD_(E_2)=-39.99,95%CI[-53.45,-26.52],P<0.05; WMD_(FSH)=-3.79,95%CI[-4.86,-2.72],P<0.05), uterine size(WMD=-50.02,95%CI[-55.98,-44.06],P<0.05), fibroids size(WMD=-15.79,95%CI[-18.11,-13.46],P<0.05) and adverse reactions(RR=0.65,95%CI[0.48,0.88],P<0.05) of trial group were all lower than those of control group, with statistical significances. Trial sequential analysis(TSA) was performed by using TSA 0.9 software, and showed a reliable therapeutic effect of the experimental group. In short, our study indicated that modified Xuefu Zhuyu Decoction combined with Western medicine had a better therapeutic effect on leiomyoma than Western medicine alone, but more high-quality studies are needed to verify this conclusion in the future.

Computational analysis of binding free energies, hotspots and the binding mechanism of Bcl-xL/Bcl-2 binding to Bad/Bax.

The anti-apoptotic proteins B-cell lymphoma-extra large (Bcl-xL) and B-cell lymphoma/leukemia-2 (Bcl-2) are members of the Bcl-2 protein family, and they play important roles in regulating apoptosis and cell cycle retardation. However, the binding mechanisms of Bcl-xL/Bcl-2 with their associated agonists, including Bcl-2-associated death promoter (Bad) and Bcl-2-associated X protein (Bax), are not well understood. In the present study, the recently developed interaction entropy approach was employed for the calculation of entropic contribution, and the computational alanine scanning method was used to identify the hot spot in the protein-protein interactions between Bcl-xL/Bcl-2 and Bad/Bax. The calculated binding free energies and their ranks for the four systems were in good agreement with the experimental results. Computational analysis shows that there are more hot-spot residues in the Bcl-xL/Bad complex than that in the Bcl-xL/Bax complex, leading to a stronger binding affinity in the former. It is interesting to find that the reason for the stronger binding affinity of Bcl-2 to Bad than to Bax is different for the Bcl-xL system. Although there are more hot-spot residues in the Bcl-2/Bax system than in the Bcl-2/Bad complex, there are also more negatively contributing residues in the Bcl-2/Bax. Our study identified Arg104, Tyr105, Leu116, and Leu134 to be the common key residues in the Bcl-xL complexes, and Arg107, Tyr108, Phe112, Gln118, Leu137, Arg146, and Tyr202 are common key residues in the Bcl-2 complexes. These results would provide valuable information for the design of potent inhibitors of Bcl-xL/Bcl-2.