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Rising evidence has shown the development of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors in the practices of cancer therapy. It is reported that the efficacy of axitinib (AX), a VEGFR inhibitor, is limited in the treatment of breast cancer as a single agent or in combination with other chemotherapeutic drugs due to the probability of rising population of cancer stem-like cells (CSCs) caused by AX. The present study evaluated the effect of dopamine (DA) improving AX's efficacy on MCF-7/ADR breast cancer in vitro and in vivo, and developed a pharmacokinetic-pharmacodynamic (PK-PD) model describing the in vivo experimental data and characterizing the interaction of effect between AX and DA. The results showed that AX up-regulated the expression of breast CSC (BCSC) markers (CD44 + /CD24 -/low ) in vivo, and DA significantly synergized the inhibitory effect on tumor growth by deducting the BCSC frequency. The PK-PD model quantitatively confirmed the synergistic interaction with the parameter estimate of interaction factor ψ 2.43. The dose regimen was optimized as 60 mg/kg AX i.g. b.i.d. combined with 50 mg/kg DA i.p. q3d in the simulation study on the basis of the PK-PD model. The model where DA synergistically enhances the effect of AX in an all-or-none manner provides a possible solution in modeling the agents like DA. Moreover, the outcome of AX and DA combination therapy in MCF-7/ADR breast cancer provided further insight of co-administering DA in the treatment of the possible CSC-causing AX-resisting breast cancer. And this combination therapy has the prospect of clinical translation.

Identifying sensitive and specific biomarkers for early detection of cancer is immensely imperative for early diagnosis and treatment and better clinical outcome of cancer patients. This study aimed to construct a specific DNA methylation pattern of cancer suppressor genes and explore the feasibility of applying cell-free DNA based methylation as a biomarker for early diagnosis of esophageal squamous cell carcinoma (ESCC). We recruited early stage ESCC patients from Yangzhong County, China. The Illumina Infinium 450K Methylation BeadChip was used to construct a genome-wide DNA methylation profile. Then, differentiated genes were selected for the validation study using the Sequenom MassARRAY platform. The frequency of methylation was compared between cancer tissues, matched cell-free DNAs and normal controls. The specific methylation profiles were constructed, and the sensitivity and specificity were calculated. Seven CG sites in three genes CASZ1, CDH13 and ING2 were significantly hypermethylated in ESCC as compared with normal controls. A significant correlation was found between the methylation of DNA extracted from cancer tissues and matched plasma cell-free DNA, either for individual CG site or for cumulative methylation analysis. The sensitivity and specificity reached 100% at an appropriate cut-point using these specific methylation biomarkers. This study revealed that aberrant DNA methylation is a promising biomarker for molecular diagnosis of esophageal cancer. Hypermethylation of CASZ1, CDH13 and ING2 detected in plasma cell-free DNA can be applied as a potential noninvasive biomarker for diagnosis of esophageal cancer.

Aims: Postmenopausal osteoporosis is a bone metabolism disease that is caused by an imbalance between bone-resorbing osteoclast and bone-forming osteoblast actions. Herein, we describe the role of troxerutin (TRX), a trihydroxyethylated derivative of rutin, in ovariectomy (OVX)-induced osteoporosis and its effects on the regulation of osteoclasts and osteoblasts., Main Methods: In vivo, OVX female mice were intraperitoneally injected with either saline, 50 mg/kg TRX, or 150 mg/kg TRX for 6 weeks and then sacrificed for micro-computed tomography analyses, histological analyses, and biomechanical testing. In vitro, RAW264.7 cell-derived osteoclasts and MC3T3-E1 cell-derived osteoblasts were treated with different concentrations of TRX to examine the effect of TRX on osteoclastogenesis and bone resorption, as well as on osteogenesis and mineralization., Key Findings: In this study, we demonstrated that TRX prevented cortical and trabecular bone loss in ovariectomized mice by reducing osteoclastogenesis and promoting osteogenesis in vivo. In vitro, TRX inhibited the formation and activity of RAW264.7-derived osteoclasts and the expression of nuclear factor of activated T-cells 1 and cathepsin K. Meanwhile, TRX improved the osteogenesis and mineralization of MC3T3-E1 by enhancing the expression of Runt-related transcription factor 2, Osterix, and collagen type 1 alpha 1., Significance: Our data demonstrated that TRX could prevent OVX-induced osteoporosis and be used in a novel treatment for postmenopausal osteoporosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Incorporation of CO 2 into heterocyclic compounds (i.e., 2-oxazolidinones) under mild conditions, especially at atmospheric pressure still remains challenging. The mononuclear Zn II complex ZnCl 2 (TBD) 2 , where TBD=1,5,7-triazabicyclo[4.4.0]dec-5-ene, in this study was demonstrated as a robust catalyst for the carboxylative cyclization of propargylic amines with CO 2 to exclusively afford various 2-oxazolidinones in excellent yields. Notably, the Zn II catalytic species is readily generated in situ from ZnCl 2 and TBD without pre-preparation and further isolation. Such a CO 2 fixation protocol could proceed smoothly under atmospheric pressure at mild temperature in an atom economic and environmentally benign manner. 13 C NMR and control experiments were performed to explore the possible interaction between Zn II and the carbon-carbon triple bond of propargylic amine. The dual catalytic role of the Zn catalyst to enhance O-nucleophilicity of the carbamate anion intermediate and activate the carbon-carbon triple bond is proposed based on mechanistic investigations., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Context: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is one of the most complicated morbidities among patients with end-stage renal disease. At present, a specific questionnaire assessing relevant knowledge and behavior for patients with CKD-MBD is still unavailable., Objectives: To develop and evaluate a valid and reliable questionnaire specific to patients with CKD-MBD., Methods: Both quantitative and qualitative analyses were combined to develop and estimate the CKD-MBD knowledge and behavior (CKD-MBD-KB) questionnaire. Three hundred thirteen and 295 patients, respectively, participated in the investigation during the period from November 2013∼October 2014. Reliability and validity testing were conducted to analyze the psychometric properties of questionnaire., Results: The final version of the CKD-MBD-KB questionnaire encompasses two domains, five facets, and 50 items. Reliability analysis showed that the Cronbach alpha of the five facets ranged from 0.578 to 0.854. Retest correlation coefficients of the five facets ranged from 0.825 to 0.944. Nine common factors were extracted from exploratory factor analysis that interpreted the cumulative variation of 64.1%, and factor loadings of all items were greater than 0.4. The results of confirmatory factor analysis indicated that the model had a satisfactory goodness of fit; the root mean square error of approximation = 0.070. Meanwhile, a significant correlation was found between each item and its facet., Conclusion: This CKD-MBD-KB questionnaire has been confirmed to have adequate psychometric properties (good reliability and validity) and may be useful in the assessment of patient-related knowledge, intervention programs, and treatment protocols., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Sclerosing cholangitis (SC) is a rarely reported morbidity secondary to transcatheter arterial chemoembolization (TACE) with bleomycin-iodinated oil (BIO) for liver cavernous hemangioma (LCH). This report retrospectively evaluated the diagnostic and therapeutic course of a patient with LDH who presented obstructive jaundice 6 years after TACE with BIO. Preoperative imaging identified a suspected malignant biliary stricture located at the convergence of the left and right hepatic ducts. Operative exploration demonstrated a full-thickness sclerosis of the hilar bile duct with right hepatic duct stricture and right lobe atrophy. Radical hepatic hilar resection with right-side hemihepatectomy and Roux-en-Y hepaticojejunostomy was performed because hilar cancer could not be excluded on frozen biopsy. Pathological results showed chronic pyogenic inflammation of the common and right hepatic ducts with SC in the portal area. Secondary SC is a long-term complication that may occur in LCH patients after TACE with BIO and must be differentiated from hilar malignancy. Hepatic duct plasty is a definitive but technically challenging treatment modality for secondary SC.

Objective: To demonstrate the pharmacokinetic profile of meropenem when administered by 3-hour infusion in patients undergoing continuous veno-venous hemofiltration (CVVH)., Methods: The study was conducted in 10 patients, who were treated with CVVH. Each subject received meropenem in 3-hour infusion of 500 mg every 6 hours. Blood samples were collected before infusion (0 hour) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6 hours (just before the infusion of the next dose) after the beginning of the fourth infusion. The concentrations of meropenem in plasma were measured by high-performance liquid chromatography method, and mean serum meropenem concentration-time curve was plotted., Results: Peak plasma drug concentrations measured 3 hours post-infusion were (25.05 ± 5.64) mg/L, and trough levels after 6 hours of infusion were (13.03 ± 3.01) mg/L. The area under the plasma concentration-time curve (AUC) was (118.42 ± 26.78) mg x h⁻¹ x L⁻². The elimination half-life (T1/2) was (3.74 ± 0.55) hours. The mean residence time (MRT) was (4.99 ± 0.84) hours. The volume of distribution (Vb) was (22.85 ± 9.85) L and clearance of meropenem (CL) was (4.49 ± 1.32) L/h. The percentage of time that the serum drug concentration was above the minimum inhibitory concentration (MIC) accounting for the interval time of infusion (%T>MIC) was 100% (MIC 8 mg/L) in all the 10 patients., Conclusion: Based on these data, we concluded that satisfactory pharmacodynamic parameters could be attained in CVVH patients treated with meropenem by a prolonged infusion time of 3 hours with a dosage of 500 mg for every 6 hours.

Objective: To study the Th17/Treg (regulatory T cells) immunoregulation in patients coinfected with TB and HIV before and after HAART(highly active anti-retroviral therapy)., Methods: 10 HIV cases coinfected with TB (HIV/TB group) and 10 cases infected with HIV only (HIV group) received HAART. PBMCs were stained and immunophenotyping of Th17 (IL-17 expressing T cells) and CD4+ CD25 T cells (Treg) were analysed by flow cytometry., Results: The pre-treatment patients tended to have lower Th17 cells and higher Tregs cells compared to post-treatment (1.90% +/- 0.9% vs. 4.65% +/- 1.48%, 16.48% +/- 4.91% vs. 8.29% +/- 3.13% respectively). The percentage of IL-17 before and after HAART were 1.90 +/- 0.9% vs. 4.65 +/- 1.48% respectively in HIV/TB group patients (P < 0.01). The difference between the percentage of IL-17 before and after HAART in the HIV/TB group and the HIV group were 2. 65 +/- 1.62% vs. 0.67% +/- 0.46% respectively (P < 0.01). IL-17 expressing T cells were increased faster after HAART in the former group than the latter. The percentage of Treg before and after HAART were 16.48% +/- 4.91% vs. 8.29% +/- 3.13% respectively in HIV/TB group (P < 0.01). The difference between the percentage of Treg before and after HAART in the HIV/TB group and the HIV group were 8.91% +/- 4.82% vs. 2.63% +/- 2.34% respectively (P < 0.01). Treg were decreased more rapidly after HAART in the former than the latter., Conclusions: TB and HAART both had an effect on the Th17/Treg ratio of HIV/ TB co-infected patients, which can cause increased Th17 expression, the later plays a pro-inflammatory role. TB and HAART can decrease Treg expression and enhance anti-inflammation response. The fact that Th17/ Treg disorder are more likely to exist in patients with HIV/TB co-infection after HAART for one month suggests a potential role for Th17/Treg imbalance leading to tuberculosis-associated immune reconstitution inflammatory syndrome during patients receiving HAART period.

A simple and specific HPLC-UV method was developed to simultaneously determine five active compounds including vitexin-4"-O-glucoside (VG), vitexin-2"-O-rhamnoside (VR), vitexin (VIT), rutin (RUT) and hyperoside (HP) in rat plasma after intravenous administrating the hawthorn leaves extract (HLE). With baicalin as internal standard (I.S.), sample pretreatment involved a one-step extraction with methanol of 0.2 ml plasma. The HPLC assay was carried out using a Phenomsil C18 analytical column with UV detection at 332 nm. The mobile phase consisted of methanol-acetonitrile-tetrahydrofuran-1% glacial acetic acid (6:1.5:18.5:74, v/v/v/v). The calibration curves were liner over the range of 2.030-500.5, 0.1513-75.64, 0.2507-12.54, 0.5128-25.64 and 0.4032-20.16 µg/ml for VG, VR, VIT, RUT and HP, respectively. The relative standard deviations (RSD) of the intra- and inter-day precisions for the analysis of the five analytes were between 1.0 and 8.9% with accuracies (relative error) below 8.2% for the analysis of the five analytes. The average extraction recoveries of five analytes were more than 82.67 ± 4.74%. The HPLC method herein described was fully validated and successfully applied to the pharmacokinetic studies after intravenous administration of HLE solution to rats over three doses.

Objective: This was an open, random, control and multicenter clinical trial. In the study, the anti-hepatic fibrosis effect of rhIFN-gamma and its side reactions were evaluated., Methods: A total of 289 patients enrolled in clinical trial, 153 patients in trial group and 136 patients in control group. The routine strategy is given in all patients. In addition, every patient in trial group received rhIFN-gamma at a dose of 1 MU intramuscularly daily for the first three months and 1 MU every other day for the following six months. Patients of two groups were followed up for another three months after the treatment. Histological indices, serum hepatic fibrosis indices, ultrasound B and symptoms and signs evaluated the effect. For patients who accepted two liver biopsies before and after treatment, the effect was determined by semiquantitative score system while for patients who did not accepted liver biopsy, serum hepatic fibrosis indices and ultrasound B were major criteria., Results: The efficient of treatment were 66% in trial group vs. 16.2% in control group and the obviously efficient of treatment was 27.8% in trial group vs. 7.4% in control group (P < 0.001). For patients who accepted two liver biopsies before and after treatment, the efficient of treatment was 63% in trial group vs. 24.1% in control group and the obviously efficient of treatment was 27.8% in trial group vs. 13.8%. For patients who did not accepted liver biopsy, the efficient of treatment was 67.7% in trial group vs. 14.0% in control group and the obviously efficient of treatment was 22.2% in trial group vs. 5.6%. None of patients emerged serious side reactions during clinical trial., Conclusion: The results confirmed that rhIFN-gamma have a better anti-hepatic fibrosis effect to patients with chronic hepatitis B.

Background & Objective: Tumor suppressor gene phosphatase and tensin homology deleted on chromosome ten (PTEN) was first reported in 1997 and has become a hot spot shortly after discovery. Mutations of PTEN gene in human hepatocellular carcinomas (HCCs) have been examined by several groups abroad, while little is known about expression of PTEN in HCCs. It has been believed that p53 mutation plays a role in the oncogenesis of HCCs. However, divergence exist as regards the relationship between p53 mutation and some biological behaviors of HCCs. The current study was designed to investigate the correlations of expression of PTEN and mutant p53 with carcinogenesis and tumor progression of HCCs., Methods: Sixty-two paraffin-embedded hepatocellular carcinoma samples were composed and all the tissue sections included both HCC and surrounding non-tumor liver tissues. Expression of PTEN and mutant p53 was examined using SP immunohistochemical technique., Results: All sixty-two samples showed decidedly positive staining of PTEN in surrounding non-tumor liver tissues (plasma). While, only twenty-nine tumors were detected positive staining of PTEN (46.8%). The expression level of PTEN in HCC samples without invasiveness or with complete capsule was higher than that in HCC samples with invasiveness or without complete capsule. No positive staining of p53 was detected in surrounding non-tumor liver tissues for all sixty-two samples. However, twenty-one tumors showed positive staining of p53 (nucleon). The expression level of p53 protein was not related with invasion or differentiation of HCCs., Conclusion: Loss of PTEN expression and mutation of p53 may play a role in occurrence of HCCs. Loss of PTEN expression may be pertinent to deterioration of HCCs.