The role of TLR4/MyD88/NF-κB in the protective effect of ulinastatin on the intestinal mucosal barrier in mice with sepsis.

OBJECTIVE: To investigate the effect of the TLR4/MyD88/NF-κB (Toll-like receptor 4/myeloid differentiation factor/nuclear factor kappa B) signalling pathway on the protective effect of ulinastatin on the intestinal mucosal barrier in mice with sepsis. METHODS: A mouse model of sepsis was established by classical caecal ligation and perforation. Forty-four SPF C57BL/6 mice were randomly divided into the following four groups with 11 mice in each group: the control group (Con group), ulinastatin group (Uti group), Uti + LPS (lipopolysaccharide, LPS) group (Uti + LPS group) and LPS group. Mice in the Con group and Uti group received saline or ulinastatin injected 2 h after modelling; Mice in the Uti + LPS group received LPS injected 0 h after modelling, other procedures were the same as in the Uti group; Mice in the LPS group received LPS only. At 48 h after surgery, the levels of TNF-α (tumour necrosis factor-α, TNF-α), IL-6 (interleukin-6, IL-6) and IL-1ß (interleukin-1ß, IL-1ß) in vein, and the expression of TLR4, MyD88 and NF-κB mRNA in small intestinal mucosa tissues using ELISA and RT‒PCR. RESULTS: The pathological specimens showed increased inflammatory injury in the Con and LPS groups, while these injuries and changes improved in the Uti group. The scores of intestinal mucosal injury at 48 h of Uti injection were significantly lower than those of the Con group (P < 0.001), while the scores of intestinal mucosal injury of Uti + LPS were significantly higher than those of the Uti group (P = 0.044). The expression of TNF-α, IL-6 and IL-1ß in the Uti decreased significantly at 48 h after surgery than that in the Con group (P = 0.001, P = 0.014, P = 0.004), while the expression of TNF-α, IL-6 and IL-1ß in the Uti + LPS group increased significantly after surgery than that in the Uti group (P = 0.026, P = 0.040, P = 0.039). The expression of TLR4, MyD88 and NF-κB mRNA in the Uti group decreased significantly compared with that in the Con group (P = 0.001, P = 0.021, P = 0.007), while the expression of TLR4, MyD88 and NF-κB mRNA in the Uti + LPS group was higher than that in the Uti group (P = 0.023, P = 0.040, P = 0.045). CONCLUSION: These findings indicate that the protective effect of ulinastatin on the intestinal mucosal barrier against sepsis may be mediated through the TLR4/MyD88/NF-κB pathway.

High endothelial venules proportion in tertiary lymphoid structure is a prognostic marker and correlated with anti-tumor immune microenvironment in colorectal cancer.

BACKGROUND: High endothelial venules (HEV) and tertiary lymphoid structures (TLS) are associated with clinical outcomes of patients with colorectal cancer (CRC). However, because HEV are components of TLS, there have been few studies of the role of the HEV proportion in TLS (HEV/TLS). This study investigated the role of the HEV/TLS and its relationship with the tumor immune microenvironment in CRC. METHODS: A retrospective analysis of 203 cases of tissue pathologically diagnosed as CRC after general surgery was performed at the First Affiliated Hospital of Jinan University from January 2014 to July 2017. Paraffin sections were obtained from the paracancerous intestinal mucosal tissues. The area of HEV and TLS and immune cells were detected by immunohistochemistry. We further divided the positive HEV expression group into the high HEV/TLS group and the low HEV/TLS group by the average area of HEV/TLS. After grouping, the data were also analyzed using the chi-square test, Kaplan-Meier method, and univariate and multivariate Cox proportional risk regression analyses. A correlation analysis of the HEV/TLS and immune cells as well as angiogenesis was performed. RESULTS: Patients with a high HEV/TLS in CRC tissue were associated with longer OS, DFS and lower TNM stage. Meanwhile, CRC tissue with a high HEV/TLS showed a greater ability to recruit the CD3+ T cells, CD8+ T cells and M1 macrophages and correlated with less angiogenesis. Conclusively, high HEV/TLS links to the favorable prognosis of CRC patients and correlated with anti-tumor immune microenvironment, which can be a potential biomarker for prognosis of CRC patients. CONCLUSION: A high HEV/TLS is associated with a favorable prognosis for CRC and is correlated with the anti-tumor immune microenvironment. Therefore, it is a potential biomarker of the CRC prognosis.KEY MESSAGESHigh HEV/TLS is associated with a favorable prognosis for CRC.High HEV/TLS correlated with the anti-tumor immune microenvironment of CRC and can serve as a novel prognostic biomarker.

A Comparative Study on Sedation Efficacy Between General and Regional Anesthesia with Dexmedetomidine in Patients Under Maxillofacial Surgery.

BACKGROUND AND OBJECTIVE: Securing the airway in the surgery of maxillofacial disorders and traumas is fundamental during the operation. The present study aims to investigate the beneficial sedative effects of dexmedetomidine (DEX) in patients who underwent maxillofacial surgery with regional anesthesia compared to general anesthesia. METHODS: Fifty patients, aged 20-45 years old were randomly divided into two groups of regional anesthesia (RA) and general anesthesia (GA) (each n=25). The group RA received regional block with sedation (DEX: 1 µg/kg infused over 10 min followed by the maintenance dose of 0.5 µg/kg/h) and the group GA underwent general anesthesia (DEX: 0.1 µg/kg/min over 10 min followed by 0.4-0.7 µg/kg/h). Postoperative pain scores, anesthesia outcomes, hemodynamic parameters, the time of the post-anesthesia care unit (PACU) discharge and intra and postoperative complications were comparatively assessed in both groups. RESULTS: The baseline characteristics of the patients (age, gender, BMI, and ASA physical status) showed no differences between the two groups (P>0.05). Although the duration of surgery and recovery time showed no differences between the groups, the duration of anesthesia and extubation time was remarkably lower in the RA group than in the GA group (P<0.01). Administration of nerve blocks demonstrated less pain and longer sleep time in the postoperative phase as compared to the GA group. Heart rate and mean arterial blood pressure were significantly less in the RA group at the end of the loading dose of DEX and incision time (P<0.05). SpO2, respiration rate and Ramsay sedation scale did not exhibit any significant differences between the two groups at all-time points (P>0.05). No significant differences were observed with regard to the adverse events between the two groups (P>0.05). CONCLUSIONS: Although our findings revealed that both methods are suitable and safe methods for maxillofacial surgery, the outcomes of anesthesia with regional block and sedation include less pain in the postoperative phase, shorter extubation time and earlier discharge from the PACU demonstrated that this method is more reliable for maxillofacial surgery. Further controlled studies are needed to compare the effectiveness and safety profiles of two RA and GA techniques and also to compare DEX with other anesthetic agents to achieve optimum outcomes in maxillofacial surgeries.

Associations of CD14 variants with the triglyceride levels and risk of myocardial infarction in an Eastern Chinese Han population.

BACKGROUND: CD14 is crucial in the progression of myocardial infarction (MI). Several studies have explored the association between the risk of MI and the CD14 C-260 T polymorphism, but have reported inconsistent results. METHODS: This study analyzed the association of the CD14 C-260 T polymorphism with susceptibility to MI. Totally, 240 MI patients and 298 normal subjects were included. The association between MI risk and the target polymorphism was assessed using 95% confidence intervals and odds ratios obtained through logistic regression. RESULTS: The T allele of the CD14 C-260 T polymorphism was linked with an elevated risk of MI in Chinese Han people; subgroup analysis indicated that this effect was associated with smoking, male gender, and hypertension. In addition, the data revealed that different genotype carriers of the CD14 C-260 T polymorphism showed significantly distinct TG levels in MI patients. CONCLUSION: Totally, the T allele of the CD14 C-260 T polymorphism is associated with an elevated risk of MI.

Penisarins A and B, Sesquiterpene Coumarins Isolated from an Endophytic Penicillium sp.

Penisarins A (1) and B (2), sesquiterpene coumarins with an unusual tricyclic sesquiterpene system, were isolated from endophytic Penicillium sp. KMU18029. Their structures were elucidated on the basis of spectroscopic methods, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compound 2 showed significant cytotoxicities against two human cancer cell lines, HL-60 and SMMC-7721, with IC50 values of 3.6 ± 0.2 and 3.7 ± 0.2 µM, respectively.

Virtual Screening for Type II B Inhibitors of B-RafV600E Kinase.

BACKGROUND: B-RafV600E kinase was identified as an important target in current cancer treatment, and the type II B inhibitors show good qualities in preclinical studies. Therefore, it is very important to discover novel II B inhibitors of B-RafV600E kinase. METHODS: In order to discover novel II B inhibitors of B-RafV600E kinase, virtual screening against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3DQSAR model and binding free energy (ΔGbind) calculation studies. The inhibitory activities against A375 cell lines of the hit compounds were tested by using MTT assay. RESULTS: Five promising hit compounds were obtained after screening, and all the five hit compounds showed good inhibitory rates against A375 cell lines. CONCLUSION: The combined approach of the virtual screening in our work is effective, which can be used to discover novel inhibitors with a new skeleton. In addition, the five compounds obtained from the screening showed good inhibitory rates against A375 cell lines, which can be considered to develop new II B inhibitors of B-RafV600E kinase.

Virtual screening of B-Raf kinase inhibitors: A combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy calculation studies.

B-Raf kinase has been identified as an important target in recent cancer treatment. In order to discover structurally diverse and novel B-Raf inhibitors (BRIs), a virtual screening of BRIs against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy (ΔGbind) calculation studies in this work. After the virtual screening, six promising hit compounds were obtained, which were then tested for inhibitory activities of A375 cell lines. In the result, five hit compounds show good biological activities (IC50<50µM). The present method of virtual screening can be applied to find structurally diverse inhibitors, and the obtained five structurally diverse compounds are expected to develop novel BRIs.

External application of traditional Chinese medicine in the treatment of bone cancer pain: a meta-analysis.

BACKGROUND: Bone cancer pain presents a clinical challenge with limitations of current treatments. Many patients seek additional therapies that may relieve pain. Many external applications of traditional Chinese medicines (EAs-TCMs) have been evaluated in clinical trials, but fewer are known about them outside of China. The objective of this study is to assess the efficacy for bone cancer pain. METHODS: A systematic literature search was conducted in seven databases until December 2014 to identify randomized controlled trials (RCTs) about EAs-TCMs in the treatment of bone cancer pain. The primary outcome was total pain relief rate. The secondary outcomes were adverse events at the end of treatment course. The methodological quality of RCTs was assessed independently using six-item criteria according to the Cochrane Collaboration. All data were analyzed using Review Manager 5.2.0. We included any RCTs evaluating an EA-TCM for the treatment of bone cancer pain. We conducted a meta-analysis. RESULTS: We included six RCTs with 534 patients. In general, the reporting of methodological issues was poor. Compared with morphine sulfate sustained release tablets (MSSRTs) or radiotherapy or bisphosphonates, we analyzed data from five trials reporting on complete response effect score (relative risk (RR) = 5.38, 95% confidence interval (CI) = 2.80-10.31, P < 0.00001) and partial response (RR = 1.18, 95% CI = 1.02-1.37, P = 0.02) and six trials reporting on total pain relief rate (RR = 1.49, 95% CI = 1.43-1.67, P < 0.00001). Six RCTs showed significant effects of EA-TCM for improving pain relief in patients with bone cancer pain. In addition, no severe adverse events were found. CONCLUSION: This systematic review showed positive but weak evidence of EA-TCM for bone cancer pain because of the poor methodological quality and the small quantity of the included trials. Future rigorously designed RCTs are required.

Application of breast ultrasound in a mammography-based Chinese breast screening study.

We evaluated the clinical significance of the combined use of mammography + ultrasound as a new breast screening strategy. The inclusion criteria were: (1) females aged >40yrs; (2) breast cancer diagnosis by the breast image screening personnel at FUSCC; (3) screening by both ultrasound and mammography; (4) mammographic/sonographic images analyzed independently by different radiologists; and (5) follow-up for at least 1 year. Fifty-four women were enrolled. The analysis included diagnostic sensitivity of mammography, ultrasound, and mammography + ultrasound. The sensitivities of mammography and mammography + ultrasound were compared overall as well as among different age groups/breast densities. The screening sensitivity of mammography, ultrasound, and mammography + ultrasound was 79.6, 57.4, and 92.6 %, respectively. The difference between mammography and mammography + ultrasound was significant (P < 0.05). The benefit of including ultrasound with mammography as a new breast image screening strategy was found statistically significant in patients with dense breast on mammogram while it was non-significant in younger (<50 years) women. We, therefore, concluded that mammography + ultrasound increased the diagnostic sensitivity of breast screening; hence it was more desirable for women with dense breast on mammography.

Multistage processing procedure for 4D breast MRI segmentation.

Contrast-enhanced magnetic resonance imaging (MRI) is a novel approach to detect breast tumor, however, multiple 3D image sets need to be analyzed which causes unaffordable inspection tasks to physicians. Computer assistant detection is of great help to this situation and image segmentation is most important process of computer assistant detection. To segment the breast region from 3D MRI set, a multistage image processing procedure was proposed. Considering the morphological features of breast image, the image was divided into two parts to reduce the complexity of the segmentation procedure. For the anterior part of the image, the breast tissue was segmented from background using the region growing method. Meanwhile, the mean intensity of breast tissue was estimated. To segment the posterior part of the image, the estimated mean breast intensity was used to initialize an approximate boundary between breast and chest. The estimated intensity distribution of breast tissue was used to set the propagation term of following level set iterations. Based on this initialization, threshold-based 3D level set algorithm was used to seek the precise boundary between chest and breast. The level set algorithm achieves novel performance for the 3D segmentation of chest boundary. Based on the segmentation of one set of 3D image, the segmentation result was used as the initial boundary of following image sets to achieve automatic 4D segmentation. This multistage procedure greatly accelerates the convergence of the level set algorithm and reduces the chance of running into local minimum. Clinical data demonstrated that this processing procedure was effective for automatic segmentation of 4D breast MRI.

Segmentation of the breast region in mammograms using watershed transformation.

The author proposes a new approach for the breast region segmentation for the purpose of reduction of subsequent processing calculation and removal of radiopaque artifacts. The proposed algorithm combines the global thresholding method for a coarse estimation of breast region and morphological operations for exact positioning of the breast boundary. 204 mammographic images were randomly selected from the DDSM mammogram database to test the segmenting algorithm and the segmentation results were evaluated by an experienced radiologist. Nearly 95% of the segmentation results were rated as exact segmentation.