Quercetin Covalently Linked Lipid Nanoparticles: Multifaceted Killing Effect on Tumor Cells.

The encapsulation of hydrophobic drugs is a problem that many researchers are working on. The goal of this study is to achieve the delivery of hydrophobic drugs by means of prodrugs and nanoformulations for a stronger tumor cell-killing effect and explore related killing mechanisms. Lipophilic quercetin (Qu) was covalently linked to glyceryl caprylate-caprate (Gcc) via disulfide bonds-containing 3,3'-dithiodipropionic acid (DTPA) to synthesize novel lipid Qu-SS-Gcc. Qu-SS-Gcc lipid nanoparticles (Qu-SS-Gcc LNPs) were fabricated using the solvent diffusion technique. The intracellular release of Qu by cleavage of nanocarriers was determined by liquid chromatography and compared with the uptake of free Qu. Detection methods, such as fluorescent quantitation, flow cytometry, and western blot were applied to explore the action mechanism induced by Qu. It was revealed that Qu-SS-Gcc LNPs could be cleaved by the high concentrations of reduction molecules in MCF-7/ADR (human multidrug-resistant breast cancer) cells, followed by the release of Qu. The intracellular Qu content produced by dissociation of Qu-SS-Gcc LNPs was higher than that produced by internalization of free Qu. The resulting release of Qu exerted superior cell-killing effects on MCF-7/ADR cells, such as P-gp inhibition by binding to P-gp binding sites, blocking the cell cycle in the G2 phase, and causing cell apoptosis and autophagy. Moreover, it was revealed autophagy triggered by a low concentration of Qu-SS-Gcc LNPs was beneficial to cell survival, while at a higher concentration, it acted as a cell killer. Qu-SS-Gcc LNPs can realize massive accumulation of Qu in tumor cells and exert a multifaceted killing effect on tumor cells, which is a reference for the delivery of hydrophobic drugs.

Chitosan-modified lipid nanodrug delivery system for the targeted and responsive treatment of ulcerative colitis.

Targeted and sensitive drug release at the colitis site is critical for the effective therapy of ulcerative colitis and reduction of side effects from the drug. Herein, we used 3,3'-dithiodipropionic acid (DTPA) to covalently link quercetin (Qu) and glyceryl caprylate-caprate (Gcc) via ester bonds to prepare Qu-SS-Gcc lipid nanoparticles (Qu-SS-Gcc LNPs). Dexamethasone (Dex) was used as a model drug, and chitosan (CSO) was modified on the surface of Qu-SS-Gcc LNPs to obtain CSO-modified Dex-loaded Qu-SS-Gcc LNPs (CSO/Dex/LNPs). The encapsulation efficiency and drug loading of CSO/Dex/LNPs were 93.1 % and 8.1 %, respectively. The in vitro release results showed that CSO/Dex/LNPs had esterase-responsive characteristics and could release the drug rapidly in esterase-containing artificial intestinal fluid. A human colorectal adenocarcinoma cell (Caco-2) monolayer was used as the intestinal cell barrier model. Transmembrane resistance measurements and permeation experiments showed that CSO/Dex/LNPs had a protective effect on the lipopolysaccharide (LPS)-stimulated Caco-2 cell monolayer and increased the expression of E-cadherin in LPS-stimulated Caco-2 cells. Moreover, CSO/Dex/LNPs could significantly reduce the expression of the inflammatory factors TNF-α, IL-6 and NO in LPS-stimulated RAW 264.7 cells. The ulcerative colitis mouse model was constructed by using C57BL/6 mice. The in vivo distribution results showed that CSO/Dex/LNPs had colon-targeting effects and strong retention ability in the colons of mice with colitis. The results also showed that CSO/Dex/LNPs had better anti-inflammatory effects than free Dex, which could reduce colonic atrophy, reduce histomorphological changes and increase the expression of E-cadherin in the colon. Furthermore, the expression levels of TNF-α, IL-6 and NO in the CSO/Dex/LNP-treated group were 37.4 %, 35.5 % and 33.2 % of those in mice with colitis, respectively.

Z-Score Reference Ranges for the Offset of the Tricuspid Septal Leaflet in Normal Fetuses.

OBJECTIVES: To determine Z-score equations and reference ranges for mitral valve-tricuspid valve distance (MTD) and the MTD index in the fetal heart. METHODS: A prospective cross-sectional study was performed in 899 normal singleton fetuses from 14 to 40 weeks' gestation. The MTD and interventricular septum length (IVSL) were measured offline after electronic cardiac spatiotemporal image correlation volume acquisition. The MTD index was determined as the ratio of MTD to IVSL. Z-score reference ranges of these measurements were determined against gestational age (GA) and estimated fetal weight (EFW), using regression analysis of the mean and standard deviation (SD). RESULTS: Strong positive correlations were found between the MTD and the independent variables. A simple linear regression model was the best description of the mean and SD of MTD based on GA, while a cubic regression best fitted the mean MTD against EFW. In contrast, the MTD index decreased progressively with the independent variables. Fractional polynomials best fitted the MTD index in terms of GA and EFW. CONCLUSION: Normal reference values and Z-scores of fetal MTD and MTD index were provided against GA and EFW, which may be useful tools for quantitative assessment of some cardiac and extracardiac diseases.

[Sonographic features and diagnostic analysis of breast granulomatous diseases: a report of 32 cases].

OBJECTIVE: To evaluate the sonographic features of different pathological types of breast granulomatous diseases and analyze the feasibility of ultrasonic diagnosis. METHODS: A total of 32 patients with different pathological types of breast granulomatous diseases were recruited. Their clinical and sonographic findings were retrospectively reviewed. There were granulomatous mastitis (n = 12), breast xanthogranuloma (n = 5), lipogranuloma (n = 2), foreign body granuloma (n = 1) and nonspecific granulation hyperplasia (n = 12). RESULTS: Based on major sonographic appearances, they were divided into 4 patterns of tubular, mass, diffuse and cystic mass. In 12 patients with granulomatous mastitis and 12 patients with nonspecific granulation hyperplasia, the major sonographic appearance was of tubular pattern (n = 6, 5), followed by mass pattern (n = 4, 5) and diffuse pattern (n = 2, 2). Five patients with breast xanthogranuloma and 1 patient with foreign body granuloma all showed mass pattern. In 2 patients with lipogranuloma, one was of mass pattern and another cystic pattern. In patients with granulomatous mastitis and patients with nonspecific granulation hyperplasia, it showed a high diagnostic reliability of ultrasound. The ratio of inflammatory lesion as the first sonographic diagnosis was 10/12 and 8/12 respectively and ultrasonic BI-RADS 4b or above both only 1/12. However, the ratio of sonographic imaging in patients with xanthogranuloma and Lipogranuloma mimic breast cancer, in which ultrasonic score as breast imaging-reporting and data system (BI-RADS) 4b or above was 4/5 and 1/1 respectively. CONCLUSIONS: Ultrasound is valuable in evaluating the lesions in patients with granulomatous mastitis and nonspecific granulation hyperplasia. However a definite diagnosis is still dependent on histopathology.

[Sonographic and computed tomography features of hepatic angiomyolipoma].

OBJECTIVE: To investigate the sonographic and computed tomography (CT) features of hepatic angiomyolipoma (HAML). METHODS: Sonographic and CT findings were analyzed in 12 patients (9 females and 3 males) with pathologically proved HAML. The size, margin, location, gray scale, and color Doppler flow imaging characteristics were observed. RESULTS: HAML was located correctly with ultrasound in all patients. The sonographic features of 12 HAML included regular shape, clear margin, and three type of echoes including homogeneous hyperechoes (n=5), heterogeneous internal echoes (n=5), or homogeneous hypoechoes (n=2). The arterial flow signal was detected in two HAML. The CT findings included adipose density (n=3), soft tissue density (n=3), and mixed density (n=6). The sonographic and CT findings were correlated with the composition and distribution of fat, vessels, and smooth muscle tissue. CONCLUSIONS: Fatty tissues within HAML shows typical imaging findings. The ultrasonographic and CT have their own advantages in detecting the fatty tissue inside HAML, and therefore a combination of these two techniques may increase the diagnostic accuracy of HAML.

[Application values of four risk of malignancy indices in the preoperative evaluation of patients with adnexal masses].

OBJECTIVE: To evaluate the diagnostic values of four risk of malignancy indices (RMI) for malignant adnexal masses. METHODS: The data of 223 women with adnexal masses admitted to the Department of Obstetrics and Gynecology of Peking Union Medical College Hospital for surgical exploration between June 2008 and December 2008 were retrospectively analyzed. The sensitivity, specificity, positive predictive value and negative predictive value of RMI1, RMI2, RMI3, and RMI4 in the diagnosis of malignant adnexal masses were calculated. RESULTS: When the cutoff levels of RMI1, RMI2, RMI3 were set at 200 and RMI4 at 450, the sensitivities for diagnosing malignant adnexal masses ranged 59.0%-67.2%, the specificities ranged 94.4%-96.9 %, the positive predictive values ranged 82.0%-87.8%, and the negative predictive values ranged 90.9%-92.6%. The Youdens indexes (YI) of RMI1, RMI2, RMI3, and RMI4 were 0.559,0.606,0.576, and 0.559, respectively. RMI2 was significantly different from RMI1 (P=0.000), RMI3 (P=0.008), and RMI4 (P=0.000) in terms of diagnostic efficiency. RMI1, RMI2, RMI3, and RMI4 at a cutoff level of 75.688.679.1, 177.2 respectively, according to ROC curves, yielded sensitivities of 77.8%-82.5%, specificities of 84.6%-90.1%, positive predictive values of 69.0%-75.4%, and negative predictive values of 90.9%-92.6%; the relevant YI of RMI1, RMI2, RMI3, and RMI4 were 0.635, 0.665, 0.651 and 0.705, respectively. Under this cutoff level, the difference between RMI1, RMI2, RMI3, and RMI4 in diagnosing malignancy had no statistic significant. The primary histological types arising false negative were early stage epithelial ovarian cancer and non-epithelial ovarian cancer. The primary histological types arising false positive were endometriosis masses and degenerative sex cord-stromal tumor. CONCLUSIONS: RMIs are useful indices for the differentiation between benign and malignant pelvic diseases. Meanwhile, their cutoff levels for Chinese populations need further study.

[Possibility of PTEN expression on predicting pathologic risk factors of endometrioid adenocarcinoma before operation].

BACKGROUND & OBJECTIVE: Fully estimating pathologic risk factors is important for selecting operation and predicting prognosis for endometrioid adenocarcinoma. Phosphatase and tension homology deleted on chromosome ten (PTEN), taken as the housekeeping gene of endometrium, has the highest mutation rate in endometrioid adenocarcinoma. This study was to investigate the effect of PTEN on predicting pathologic risk factors of endometrioid adenocarcinoma before operation. METHODS: Clinicopathologic data of 107 patients with endometrioid adenocarcinoma were retrospectively analyzed. The expression of PTEN was detected by SP immunohistochemistry. Correlations of PTEN to high risk factors, such as differentiation, myometrium invasion, and lymphatic metastasis, were analyzed. RESULTS: Deletion rate of PTEN was 56.1% in the 107 endometrioid adenocarcinoma patients. PTEN expression had no correlations to histological differentiation (P=0.695), myometrium invasion (P=0.921), lymphatic metastasis (P=0.682), surgical stage (P=0.750), estrogen receptor (P=0.281), and progestin receptor (P=0.260). CONCLUSION: Detection of PTEN can't predict the high risk factors of endometrioid adenocarcinoma before operation.