Prophylactic Intra-abdominal Drainage is Associated With Lower Postoperative Complications in Patients With Crohn's Disease: A Randomized Controlled Trial.

BACKGROUND: Prophylactic intraoperative drains have been shown not superior for patients underwent intestinal surgery. However, for patients with Crohn's disease (CD), this needs further exploration. METHODS: In this pilot study, CD patients were randomly assigned to drain (n = 50) and no-drain (n = 50) groups. The primary endpoint was the rate of postoperative prolonged ileus (PPOI). The secondary endpoints were postoperative abdominal ascites, postoperative systemic inflammatory response syndrome (SIRS) and C-reactive protein (CRP) levels. RESULTS: The incidences of PPOI and postoperative abdominal ascites were significantly lower in the drain group (12% vs 44%; 0% vs 24%, both P < .05). Postoperative SIRS incidence and CRP levels were significantly increased in the no-drain group [36% vs 10%; 54.9 vs 34.3 mg/L, both P < .05]. In multivariate analysis, prophylactic drainage was the independent protective factor for PPOI and postoperative LOS. CONCLUSIONS: Prophylactic drainage may be associated with improved clinical outcomes in CD patients.

Azathioprine plus exclusive enteral nutrition versus azathioprine monotherapy for the prevention of postoperative recurrence in patients with Crohn's disease: an open-label, single-centre, randomised controlled trial.

BACKGROUND: Azathioprine (AZA) effectively prevents postoperative endoscopic recurrence (ER) in Crohn's disease (CD). However, the efficacy of AZA emerge needs 3 months. Exclusive enteral nutrition (EEN) can maintain remission for CD. The trial investigates whether AZA plus postoperative 3-month EEN is superior to AZA alone in preventing ER of CD. METHODS: Totally, 84 high-risk CD patients undergoing intestinal resection received AZA alone or AZA plus a 3-month EEN (AZA+EEN) postoperatively. The primary endpoint was the rate of ER at month 12. Secondary endpoint included the rate of ER at month 3, clinical recurrence (CR), CD activity index (CDAI) scores, fecal calprotectin (FC) and CRP. Quality of life were assessed using Short Form-36 (SF-36) and the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: The patients in the AZA+EEN group exhibited significantly lower rates of ER compared to the AZA group at both months 12 (33.3% [13/39] vs 63.2% [24/38], P=0.009) and months 3 (8.6% [3/35] vs 28.1% [9/32], P=0.037) post-surgery. The rates of CR between the two groups at month-3 and month-12 were similar. The CDAI scores, FC, albumin level and CRP were all comparable between the 2 groups. The quality of life was significantly higher in the AZA group than that of the AZA+EEN group at month 3 but became comparable from month 5 to 12 postoperatively. CONCLUSION: In high-risk CD patients, combining AZA with postoperative 3-month EEN reduces 1-year ER but may temporarily impact quality of life. Further large-scale, long-term studies are warranted.

Coordinatized lesion location analysis empowering ROI-based radiomics diagnosis on brain gliomas.

OBJECTIVES: To assess the value of coordinatized lesion location analysis (CLLA), in empowering ROI-based imaging diagnosis of gliomas by improving accuracy and generalization performances. METHODS: In this retrospective study, pre-operative contrasted T1-weighted and T2-weighted MR images were obtained from patients with gliomas from three centers: Jinling Hospital, Tiantan Hospital, and the Cancer Genome Atlas Program. Based on CLLA and ROI-based radiomic analyses, a fusion location-radiomics model was constructed to predict tumor grades, isocitrate dehydrogenase (IDH) status, and overall survival (OS). An inter-site cross-validation strategy was used for assessing the performances of the fusion model on accuracy and generalization with the value of area under the curve (AUC) and delta accuracy (ACC) (ACCtesting-ACCtraining). Comparisons of diagnostic performances were performed between the fusion model and the other two models constructed with location and radiomics analysis using DeLong's test and Wilcoxon signed ranks test. RESULTS: A total of 679 patients (mean age, 50 years ± 14 [standard deviation]; 388 men) were enrolled. Based on tumor location probabilistic maps, fusion location-radiomics models (averaged AUC values of grade/IDH/OS: 0.756/0.748/0.768) showed the highest accuracy in contrast to radiomics models (0.731/0.686/0.716) and location models (0.706/0.712/0.740). Notably, fusion models ([median Delta ACC: - 0.125, interquartile range: 0.130]) demonstrated improved generalization than that of radiomics model ([- 0.200, 0.195], p = 0.018). CONCLUSIONS: CLLA could empower ROI-based radiomics diagnosis of gliomas by improving the accuracy and generalization of the models. CLINICAL RELEVANCE STATEMENT: This study proposed a coordinatized lesion location analysis for glioma diagnosis, which could improve the performances of the conventional ROI-based radiomics model in accuracy and generalization. KEY POINTS: • Using coordinatized lesion location analysis, we mapped anatomic distribution patterns of gliomas with specific pathological and clinical features and constructed glioma prediction models. • We integrated coordinatized lesion location analysis into ROI-based analysis of radiomics to propose new fusion location-radiomics models. • Fusion location-radiomics models, with the advantages of being less influenced by variabilities, improved accuracy, and generalization performances of ROI-based radiomics models on predicting the diagnosis of gliomas.

Effects of oral immunonutritional supplement on 3-year disease-free survival in gastric cancer patients with pathological stage III after total gastrectomy (CRUCIAL): study protocol of a multicentre, randomised clinical trial.

INTRODUCTION: The nutritional status of patients with gastric cancer (GC) after total gastrectomy continues to deteriorate and lasts a long time after discharge, which is an independent risk factor for mortality. Recent guidelines have recommended appropriate nutritional support after discharge for cancer surgery patients with malnutrition or nutritional risk. The evidence on the efficacy of oral immunonutritional supplement (INS) and its effect on long-term disease-free survival (DFS) in patients with GC is limited. This study was designed to test the hypothesis that oral INS compared to diet alone may improve 3-year DFS of GC patients with pathological stage III after total gastrectomy (Nutrition Risk Screening 2002 score ≥3 at discharge). METHODS AND ANALYSIS: This is a pragmatic, open-label, multicentre, randomised controlled study. 696 eligible GC patients with pathological stage III after total gastrectomy will be randomised in a 1:1 ratio to oral INS group or normal diet group for 6 months. The primary endpoint is 3-year DFS after discharge. The following secondary endpoints will be evaluated: 3-year overall survival; unplanned readmission rate at 3 and 6 months after discharge; quality of life, body mass index and haematological index at 3, 6 and 12 months after discharge; incidence of sarcopenia at 6 and 12 months after discharge; and the tolerance to chemotherapy. The adverse events of oral INS will also be evaluated during the intervention. ETHICS AND DISSEMINATION: This study was approved by the ethics committee of Jinling Hospital, Nanjing University (number 2021NZKY-069-01). The present study may validate the effectiveness of oral immunonutritional therapy in improving 3-year DFS for GC patients with pathological stage III after total gastrectomy for the first time. The results of this trial will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: NCT05253716.

Crosstalk of Oxidative Phosphorylation-Related Subtypes, Establishment of a Prognostic Signature and Immune Infiltration Characteristics in Colorectal Adenocarcinoma.

Oxidative phosphorylation (OXPHOS) is an emerging target in cancer therapy. However, the prognostic signature of OXPHOS in colorectal adenocarcinoma (COAD) remains non-existent. We comprehensively investigated the expression pattern of OXPHOS-related genes (ORGs) in COAD from public databases. Based on four ORGs, an OXPHOS-related prognostic signature was established in which COAD patients were assigned different risk scores and classified into two different risk groups. It was observed that the low-risk group had a better prognosis but lower immune activities including immune cells and immune-related function in the tumor microenvironment. Combining with relevant clinical features, a nomogram for clinical application was also established. Receiver operating characteristic (ROC) and calibration curves were constructed to demonstrate the predictive ability of this risk signature. Moreover, a higher risk score was significantly positively correlated with higher tumor mutation burden (TMB) and generally higher gene expression of immune checkpoint, N6-methyladenosine (m6A) RNA methylation regulators and mismatch repair (MMR) related proteins. The results also indicated that the high-risk group was more sensitive to immunotherapy and certain chemotherapy drugs. In conclusion, OXPHOS-related prognostic signature can be utilized to better understand the roles of ORGs and offer new perspectives for clinical prognosis and personalized treatment.

Structural insights into ligand recognition and selectivity of somatostatin receptors.

Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of Gi1-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of Gi1-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.

Automated quantitative lesion water uptake in acute stroke is a predictor of malignant cerebral edema.

OBJECTIVES: Net water uptake (NWU) has been shown to have a linear relationship with brain edema. Based on an automated-Alberta Stroke Program Early Computed Tomography Score (ASPECTS) technique, we automatically derived NWU from baseline multimodal computed tomography (CT), namely ASPECTS-NWU. We aimed to determine if ASPECTS-NWU can predict the development of malignant cerebral edema (MCE). METHODS: One hundred and forty-six patients with large-vessel occlusion were retrospectively enrolled. Quantitative NWU based on automated-ASPECTS was measured both on nonenhanced CT (NECT) and CT angiography (CTA), namely NECT-ASPECT-NWU and CTA-ASPECTS-NWU. The correlation between ASPECTS-NWU and cerebral edema (CED) grades was calculated using Spearman rank correlation. Univariate logistic regression was used to assess the effect of radiological and clinical features on MCE, and a multivariable model with significant factors from the univariate regression analysis was built. Receiver operating characteristic (ROC) was obtained and area under curve (AUC) was compared. RESULTS: CTA-ASPECTS-NWU had a moderate positive correlation with CED grades (r = 0.62; 95% confidence interval [CI], 0.51-0.71; p < 0.001). The CTA-ASPECTS-NWU performed better than the NECT-ASPECTS-NWU with AUC: 0.88 vs. 0.71 (p < 0.001). Multivariable logistic regression model integrating CTA-ASPECTS-NWU, collateral score, and age showed the CTA-ASPECTS-NWU was an independent predictor of MCE with an AUC of 0.94 (95% CI: 0.90-0.98; p < 0.001). CONCLUSIONS: This study demonstrates that ASPECTS-NWU is a quantitative predictor of MCE after large-vessel occlusion of the middle cerebral artery territory. The multivariable logistic regression model may enhance the identification of patients with MCE needing anti-edematous treatment. KEY POINTS: • The automated-ASPECTS technique can automatically detect the affected regions with early ischemic changes and NWU could be manually calculated. • The CTA-ASPECTS-NWU performs better than the NECT-ASPECTS-NWU on predicting the development of MCE. • The multivariable logistic regression model may enhance the identification of patients with MCE needing anti-edematous treatment.

Glomus Tumors of the Distal Phalanx: A Retrospective Review of Clinical Diagnosis and Treatment.

Glomus tumors (GTs) are rare and typically occur in distal digital bones, with a majority of cases comprising benign vascular tumors. The current study retrospectively reviewed 10 cases of GTs treated by the authors between January 2009 and December 2016. In 9 cases, the GTs were subungual; 1 case was periungual. The affected fingers included 2 thumbs, 3 index fingers, 3 middle fingers, and 2 little fingers. The GTs showed characteristic signs and symptoms. All patients underwent tumor excision. Pathological examination found a thin layer of fibrous membrane surrounding the excised tumor body, which contained small vessels surrounded by multilayered tumor cells. No recurrence was seen during follow-up. The results of this study suggested the following: (1) whole tumor excision is key to preventing GT recurrence; and (2) in case of considerable phalangeal cortex erosion, K-wire fixation followed by autogenous bone grafting can produce satisfactory outcomes, although accurate evidence-based indications for this management need to be established. [Orthopedics. 2022;45(2):e101-e106.].

Prevalence and Associated Risk Factors of Pulmonary Embolism in Children and Young Adults With Nephrotic Syndrome: A Chinese Large Cohort Study.

PURPOSE: Nephrotic syndrome (NS) is highly associated with an increased risk of pulmonary embolism (PE) in children and young adults. However, few studies have specified the risk factors of PE in children and young adults with NS. We sought to determine the prevalence and associated factors of PE confirmed with computed tomography pulmonary angiography in Chinese children and young adults with NS. METHODS: Data from 444 children and young adults with NS who had computed tomography pulmonary angiography from December 2010 to October 2018 were retrospectively analyzed. The prevalence of PE was estimated for different age, sex, and histopathologic types of NS. Multivariable logistic regression was used to identify independent risk factors of PE in children and young adults with NS. Models incorporating the independent risk factors were evaluated using receiver operation characteristic curves. Area under the curve was used to determine the best-performing prognosticators for predicting PE. RESULTS: There were 444 patients in the study cohort (310 male patients, 134 female patients; mean age 19±3 y; range: 6 to 25 y). PE was present in 24.8% of the participants (110 of 444, 18.2% female). Children and young adult NS patients with PE tend to be older, male, to have a previous thromboembolism history and smoking, and have a higher level of proteinuria, D-dimer, and serum albumin (P<0.05 for all). Children and young adults with membranous nephropathy are likely to have a higher incidence of PE than those with other types of nephropathy. Membranous nephropathy and proteinuria were significant predictors of PE in children and young adults with NS (P<0.05 for all). The area under the curves of each model for the presence of PE in children and young adults with NS based on biochemical parameters and clinical information (model 1), adjusted for proteinuria (model 2), and adjusted for membranous nephropathy (model 3) were 0.578, 0.657, and 0.709, respectively. Compared with model 1, model 2, and model 3 showed statistically significant differences (model 1 vs. model 2, P=0.0336; model 1 vs. model 3, P=0.0268). There was no statistically significant difference between model 2 and model 3 (P=0.2947). CONCLUSION: This study identified membranous nephropathy and proteinuria as independent associated factors of PE in children and young adults with NS, which can be noted as a risk factor to guide clinician management in this population.

Development and validation of a clinically applicable deep learning strategy (HONORS) for pulmonary nodule classification at CT: A retrospective multicentre study.

PURPOSE: To propose a practical strategy for the clinical application of deep learning algorithm, i.e., Hierarchical-Ordered Network-ORiented Strategy (HONORS), and a new approach to pulmonary nodule classification in various clinical scenarios, i.e., Filter-Guided Pyramid NETwork (FGP-NET). MATERIALS AND METHODS: We developed and validated FGP-NET on a collection of 2106 pulmonary nodules on computed tomography images which combined screened and clinically detected nodules, and performed external test (n = 341). The area under the curves (AUCs) of FGP-NET were assessed. A comparison study with a group of 126 skilled radiologists was conducted. On top of FGP-NET, we built up our HONORS which was composed of two solutions. In the Human Free Solution, we used the high sensitivity operating point for screened nodules, but the high specificity operating point for clinically detected nodules. In the Human-Machine Coupling Solution, we used the Youden point. RESULTS: FGP-NET achieved AUCs of 0.969 and 0.847 for internal and external test. The AUCs of the subsets of the external test set ranged from 0.890 to 0.942. The average sensitivity and specificity of the 126 radiologists were 72.2 ±â€¯15.1 % and 71.7 ±â€¯15.5 %, respectively, while a higher sensitivity (93.3 %) but a relatively inferior specificity (64.0 %) were achieved by FGP-NET. HONORS-guided FGP-NET identified benign nodules with high sensitivity (sensitivity,95.5 %; specificity, 72.5 %) in the screened nodules, and identified malignant nodules with high specificity (sensitivity, 31.0 %; specificity, 97.5 %) in the clinically detected nodules. These nodules could be reliably diagnosed without any intervention from radiologists, via the Human Free Solution. The remaining ambiguous nodules were diagnosed with high performance, which however required manual confirmation by radiologists, via the Human-Machine Coupling Solution. CONCLUSIONS: FGP-NET performed comparably to skilled radiologists in terms of diagnosing pulmonary nodules. HONORS, due to its high performance, might reliably contribute a second opinion, aiding in optimizing the clinical workflow.

Machine Learning Based on Multi-Parametric MRI to Predict Risk of Breast Cancer.

PURPOSE: Machine learning (ML) can extract high-throughput features of images to predict disease. This study aimed to develop nomogram of multi-parametric MRI (mpMRI) ML model to predict the risk of breast cancer. METHODS: The mpMRI included non-enhanced and enhanced T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), apparent diffusion coefficient (ADC), K trans, K ep, V e, and V p. Regions of interest were annotated in an enhanced T1WI map and mapped to other maps in every slice. 1,132 features and top-10 principal components were extracted from every parameter map. Single-parametric and multi-parametric ML models were constructed via 10 rounds of five-fold cross-validation. The model with the highest area under the curve (AUC) was considered as the optimal model and validated by calibration curve and decision curve. Nomogram was built with the optimal ML model and patients' characteristics. RESULTS: This study involved 144 malignant lesions and 66 benign lesions. The average age of patients with benign and malignant lesions was 42.5 years old and 50.8 years old, respectively, which were statistically different. The sixth and fourth principal components of K trans had more importance than others. The AUCs of K trans, K ep, V e and V p, non-enhanced T1WI, enhanced T1WI, T2WI, and ADC models were 0.86, 0.81, 0.81, 0.83, 0.79, 0.81, 0.84, and 0.83 respectively. The model with an AUC of 0.90 was considered as the optimal model which was validated by calibration curve and decision curve. Nomogram for the prediction of breast cancer was built with the optimal ML models and patient age. CONCLUSION: Nomogram could improve the ability of breast cancer prediction preoperatively.

3D Bioprinting of shear-thinning hybrid bioinks with excellent bioactivity derived from gellan/alginate and thixotropic magnesium phosphate-based gels.

3D Bioprinting is expected to become a strong tool for regenerative medicine, but satisfactory bioinks for the printing of constructs containing living cells are lacking due to the rigorous requirement of high printability and biocompatibility, which are often contradictory. Here, we have reported the development of a novel hybrid bioink by combining rigid gellan gum (GG), flexible sodium alginate (SA), and a bioactive substance thixotropic magnesium phosphate-based gel (TMP-BG). The ratio of these components was first optimized to obtain satisfactory gelating, mechanical, rheological, and printing properties. The formulated hybrid GG-SA/TMP-BG bioink had a good printability due to the shear-thinning and its multiple cross-linking by Mg2+ and Ca2+. The tunable mechanical performance of the hybrid bioink could simulate various extracellular matrices of the different tissues and support integrity of 3D printing constructs. Moreover, the hybrid bioink induced apatite deposition during immersion in simulated body fluids, and also promoted cell proliferation in vitro. MG-63 osteosarcoma cells were dispersed in the bioink and printed into 3D constructs. The cells exhibited good cell survival due to the shear-thinning property of the bioink and the ion concentration used for cross-linking. The proliferation rate of the cells also significantly exceeded those in non-printed samples. Confocal microscopy revealed a homogeneous distribution of cells in the printed constructs, and survival for more than 7 d. In vivo animal experiments showed that the hybrid bioink without cells could induce osteochondral repair. Therefore, this hybrid bioink has good printability, biocompatibility, mechanical support, and bioactivity, which is expected to have promising applications in 3D bioprinting.

Development and validation of machine learning prediction model based on computed tomography angiography-derived hemodynamics for rupture status of intracranial aneurysms: a Chinese multicenter study.

OBJECTIVES: To build models based on conventional logistic regression (LR) and machine learning (ML) algorithms combining clinical, morphological, and hemodynamic information to predict individual rupture status of unruptured intracranial aneurysms (UIAs), afterwards tested in internal and external validation datasets. METHODS: Patients with intracranial aneurysms diagnosed by computed tomography angiography and confirmed by invasive cerebral angiograph or clipping surgery were included. The prediction models were developed based on clinical, aneurysm morphological, and hemodynamic parameters by conventional LR and ML methods. RESULTS: The training, internal validation, and external validation cohorts were composed of 807 patients, 200 patients, and 108 patients, respectively. The area under curves (AUCs) of conventional LR models 1 (clinical), 2 (clinical and aneurysm morphological), and 3 (clinical, aneurysm morphological and hemodynamic characteristics) were 0.608, 0.765, and 0.886, respectively (all p < 0.05). The AUCs of ML models using random forest (RF), multilayer perceptron (MLP), and support vector machine (SVM) were 0.871, 0.851, and 0.863, respectively. There were no difference among AUCs of conventional LR, RF, and SVM (all p > 0.05/6), while the AUC of MLP was lower than that of conventional LR (p = 0.0055). CONCLUSION: Hemodynamic parameters play an important role in the prediction performance of the models. ML methods cannot outperform conventional LR in prediction models for rupture status of UIAs integrating clinical, aneurysm morphological, and hemodynamic parameters. KEY POINTS: • The addition of hemodynamic parameters can improve prediction performance for rupture status of unruptured intracranial aneurysms. • Machine learning algorithms cannot outperform conventional logistic regression in prediction models for rupture status integrating clinical, aneurysm morphological, and hemodynamic parameters. • Models integrating clinical, aneurysm morphological, and hemodynamic parameters may help choose the optimal management.

Correlations Study Between 18F-FDG PET/CT Metabolic Parameters Predicting Epidermal Growth Factor Receptor Mutation Status and Prognosis in Lung Adenocarcinoma.

Purpose: This study assessed the ability of metabolic parameters from 18Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and clinicopathological data to predict epidermal growth factor receptor (EGFR) expression/mutation status in patients with lung adenocarcinoma and to develop a prognostic model based on differences in EGFR expression status, to enable individualized targeted molecular therapy. Patients and Methods: Metabolic parameters and clinicopathological data from 200 patients diagnosed with lung adenocarcinoma between July 2009 and November 2016, who underwent 18F-FDG PET/CT and EGFR mutation testing, were retrospectively evaluated. Multivariate logistic regression was applied to significant variables to establish a prediction model for EGFR mutation status. Overall survival for both mutant and wild-type EGFR was analyzed to establish a multifactor Cox regression model. Results: Of the 200 patients, 115 (58%) exhibited EGFR mutations and 85 (42%) were wild-type. Among selected metabolic parameters, metabolic tumor volume (MTV) demonstrated a significant difference between wild-type and mutant EGFR mutation status, with an area under the receiver operating characteristic curve (AUC) of 0.60, which increased to 0.70 after clinical data (smoking status) were combined. Survival analysis of wild-type and mutant EGFR yielded mean survival times of 34.451 (95% CI 28.654-40.249) and 53.714 (95% CI 44.331-63.098) months, respectively. Multivariate Cox regression revealed that mutation type, tumor stage, and thyroid transcription factor-1 (TTF-1) expression status were the main factors influencing patient prognosis. The hazard ratio for mutant EGFR was 0.511 (95% CI 0.303-0.862) times that of wild-type, and the risk of death was lower for mutant EGFR than for wild-type. The risk of death was lower in TTF-1-positive than in TTF-1-negative patients. Conclusion: 18F-FDG PET/CT metabolic parameters combined with clinicopathological data demonstrated moderate diagnostic efficacy in predicting EGFR mutation status and were associated with prognosis in mutant and wild-type EGFR non-small-cell lung cancer (NSCLC), thus providing a reference for individualized targeted molecular therapy.

AMOT130/YAP pathway in topography-induced BMSC osteoblastic differentiation.

Micro/nano-topography (MNT) is an important variable affecting osseointegration of bone biomaterials, but the underlying mechanisms are not fully understood. We probed the role of a AMOT130/YAP pathway in osteoblastic differentiation of bone marrow mesenchymal stems cultured on titanium (Ti) carrying MNTs. Ti surfaces with two well-defined MNTs (TiO2 nanotubes of different diameters and wall thicknesses) were prepared by anodization. Rat BMSCs were cultured on flat Ti and Ti surfaces carrying MNTs, and cell behaviors (i.e., morphology, F-actin development, osteoblastic differentiation, YAP localization) were studied. Ti surfaces carrying MNTs increased F-actin formation, osteoblastic gene expression, and protein AMOT130 production in BMSCs (all vs. flat Ti), and the surface carrying larger nantubes was more effective, confirming osteoblastic differentiation induced by MNTs. Elevation of the AMOT130 level (by inhibiting its degradation) increased the osteoblastic gene expression, F-actin formation, and nuclear localization of YAP. These show that, AMOT130/YAP is an important pathway mediating the translation of MNT signals to BMSC osteoblastic commitment, likely via the cascade: AMOT130 promotion of F-actin formation, increased YAP nuclear import, and activation of osteoblastic gene expression.

Cation Channel Transient Receptor Potential Vanilloid 4 Mediates Topography-Induced Osteoblastic Differentiation of Bone Marrow Stem Cells.

Micro/nanotopographies (MNTs) have been reported to enhance the osseointegration of biomaterials and modulate cell functions, but the underlying mechanisms are incompletely understood. We hypothesized that transient receptor potential vanilloid 4 (TRPV4) may mediate the topographically induced osteoblastic differentiation of bone marrow stem cells (BMSCs) by regulating the NFATc1 and Wnt/ß-catenin signaling. To test this hypothesis, murine BMSCs were cultured on polished titanium (Ti) discs (PT) and Ti discs carrying titania nanotubes (i.e., MNTs) with diameters of ∼30 and ∼100 nm (termed TNT-30 and TNT-100, respectively). It was found that the MNTs (in particular TNT-100) promoted the expression and activation of TRPV4. Inhibition of TRPV4 in BMSCs cultured on TNT-100 reduced the expression of osteoblastic genes and the gene expression and protein levels of NFATc1 and Wnt3a/ß-catenin and also decreased nuclear translocation of NFATc1 and ß-catenin (all vs uninhibited BMSCs). Conversely, activation of TRPV4 in BMSCs cultured on PT increased the expression of the osteoblastic gene and the gene expression and protein level of NFATc1 and Wnt3a/ß-catenin and also enhanced the nuclear translocation of NFATc1 and ß-catenin (all vs unactivated BMSCs). These differences suggest that the MNTs promoted TRPV4 expression and activation to enhance intracellular Ca2+, which further increased the nuclear translocation of NFATc1 and stimulated the Wnt/ß-catenin signaling, thus leading to upregulated expression of osteoblastic genes. These results indicate TRPV4 to be a mediator in MNT-induced osteoblastic differentiation of BMSCs.

Coptisine suppresses tumor growth and progression by down-regulating MFG-E8 in colorectal cancer.

Treating colorectal cancer (CRC) continues to be a clinical challenge. Coptisine, an alkaloid derived from Coptis chinensis Franch. shows toxic effects on CRC cells, but its underlying mechanism remains elusive. MFG-E8 is involved in tumor growth and progression. Herein, we evaluated the effects of coptisine on MFG-E8 in CRC, and explored the mechanism. The expression of MFG-E8 in CRC and adjacent normal colon tissue samples from patients was detected. The effects of coptisine on CRC cells HCT116 in vitro were evaluated by CCK-8, adhesion and transwell assays. A xenograft tumor model was used to assess the effects of coptisine in vivo. The morphology of CRC tissue was observed by HE staining. Cell signaling was tested using western blotting and immunohistochemical assay. The expression of MFG-E8 in human CRC tissue samples significantly increased compared with that of adjacent normal ones. Coptisine significantly reduced the expressions of MFG-E8 in HCT116 cells and tumor-bearing mice. Moreover, coptisine suppressed the growth, adhesion and metastasis of CRC cells. Coptisine also suppressed the expression of MMP-2 and MMP-9 via the PI3K/AKT signaling pathway. Furthermore, it inhibited epithelial-mesenchymal transition in vivo and in vitro. Coptisine inhibited CRC growth and progression by down-regulating MFG-E8, and is a potential candidate for treatment.