Background: Gallbladder lesions have become more common nowadays.But there is limited evidence-based guidance on surveillance of these patients for malignancy.Predicting malignancy could help clinicians better manage this condition and improve the prognosis.We evaluated the independent and joint effects of metabolic syndrome components on the risk of malignancy among patients with gallbladder lesions.Methods: Using a multicenter database, consecutive patients with pathologically confirmed gallbladder lesions between 2012 and 2019 were identified.Univariate and multivariate logistic regression analyses were used to evaluate the effects of metabolic syndrome components (diabetes, hypertension, dyslipidemia and obesity) as additive or combined indicators for the risk of malignancy.Unadjusted and adjusted odds ratios were calculated.Results: Of the 625 patients, 567 patients were identified with benign gallbladder lesions and 58 patients with gallbladder cancer (GBC).GBC group had less obesity but more dyslipidemia.Among all metabolic syndrome components, only dyslipidemia was significantly associated with GBC (odds ratio 2.674, 95% confidence interval 1.173-6.094).Dyslipidemia was an independent risk factor for malignancy (adjusted odds ratio 2.164, 95% confidence interval 1.165-4.021),regardless of whether the other risk factors and metabolic syndrome components were combined.Patients with decreased high-density lipoprotein had 3.035-fold higher risk of malignancy (adjusted odds ratio 3.035, 95% confidence interval 1.645-5.600).Conclusions: Dyslipidemia is associated with a 2.674-fold increase in the risk of malignancy in patients with gallbladder lesions.Dyslipidemia is an independent risk factor for malignancy, regardless of the presence of the other risk factors and metabolic syndrome components.
Mesenchymal stem/stromal cells (MSCs) present a promising tool in cell-based therapy for treatment of various diseases. Currently, optimization of treatment protocols in clinical studies is complicated by the variations in cell dosing, diverse methods used to deliver MSCs, and the variety of methods used for tracking MSCs in vivo. Most studies use a dose escalation approach, and attempt to correlate efficacy with total cell dose. Optimization could be accelerated through specific understanding of MSC distribution in vivo, long-term viability, as well as their biological fate. While it is not possible to quantitatively detect MSCs in most targeted organs over long time periods after systemic administration in clinical trials, it is increasingly possible to apply pharmacokinetic modeling to predict their distribution and persistence. This Review outlines current understanding of the in vivo kinetics of exogenously administered MSCs, provides a critical analysis of the methods used for quantitative MSC detection in these studies, and discusses the application of pharmacokinetic modeling to these data. Finally, we provide insights on and perspectives for future development of effective therapeutic strategies using pharmacokinetic modeling to maximize MSC therapy and minimize potential side effects. Stem Cells Translational Medicine 2018;7:78-86.
Background. Mesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of injury. However in vivo MSC distribution following intravenous transplantation remains poorly understood, potentially hampering the precise prediction and evaluation of therapeutic efficacy. Methods. A murine model of partial ischemia/reperfusion (I/R) is used to induce liver injury, increase the hepatic levels of SDF-1, and study in vivo MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA allow us to examine the in vivo kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize in vivo homing of human MSCs in mouse models with SDF-1 levels in liver and CXCR4 expression on the transfused MSCs. The model is calibrated to experimental data to provide novel estimates of relevant parameter values. Results. Images of immunohistochemistry for SDF-1 in the mouse liver with I/R injury show a significantly higher SDF-1level in the I/R injured liver than that in the control. Correspondingly, the ELISA results illustrate a higher MSC dose in the I/R injured liver than the normal liver. CXCR4 is overexpressed in hypoxia-preconditioned MSCs. An increased number of hypoxia-preconditioned MSCs in the I/R injured liver is observed from the ELISA results. The model simulations align with the experimental data of control and hypoxia-preconditioned human MSC distribution in normal and injured mouse livers, and accurately predict the experimental outcomes with different MSC doses. Discussion. The modelling results suggest that SDF-1 in organs is an effective in vivo attractant for MSCs through the SDF-1/CXCR4 axis and reveals the significance of the SDF-1/CXCR4 chemotaxis on in vivo homing of MSCs, especially under hypoxic preconditioning. The impact of the liver and MSC conditions on passive homing is small. This in vivo modelling approach allows qualitative characterization and prediction of the MSC homing to normal and injured organs on the basis of clinically accessible variables, such as the MSC dose and SDF-1 concentration in blood. This model could also be adapted to abnormal conditions and/or other types of circulating cells to predict in vivo homing patterns.
Chemoresistance is one of the most leading causes for tumor progression and recurrence of bladder cancer. Reactive oxygen species (ROS) plays a key role in the chemosensitivity of cancer cells. In the present study, emodin (1,3,8-trihydroxy-6-methylanthraquinone) was applied as a ROS generator in combination with cisplatin in T24 and J82 human bladder cancer cells. Cell viability and apoptosis rate of different treatment groups were detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry (FCM). The expression of transporters was measured at both the transcription and translation levels using PCR and western blotting. In vitro findings were confirmed by in vivo experiments using tumor-bearing mice. The expression of multidrug resistance-associated protein 1 (MRP1) in tumour tissue was measured using immunohistochemistry and side effects of the emodin/cisplatin co-treatment were investigated by histological examination. Emodin increased the cellular ROS level and effectively enhanced the cisplatin-induced cytotoxicity of T24 and J82 human bladder cancer cells through decreasing glutathione-cisplatin (GSH-cisplatin) conjugates. It blocked the chemoresistance of T24 and J82 cells to cisplatin through suppressing the expression of MRP1. This effect was specific in T24 and J82 cells but not in HCV-29 normal bladder epithelial cells. Consistent with in vitro experiments, emodin/cisplatin co-treatment increased the cell apoptosis and repressed the MRP1 expression in xenograft tumors, and without obvious systemic toxicity. This study revealed that emodin could increase the cisplatin-induced cytotoxicity against T24 and J82 cells via elevating the cellular ROS level and downregulating MRP1 expression. We suggest that emodin could serve as an effective adjuvant agent for the cisplatin-based chemotherapy of bladder cancer.
: Advanced hepatocellular carcinoma (HCC) with portal vein thrombosis has a poor prognosis. This study was undertaken to evaluate the therapeutic effects of intra-arterial infusion chemotherapy in advanced HCC, and tried to identify prognostic factors that could affect survival.: Between January 1995 and January 2001, a total of 102 patients with advanced HCC with portal vein thrombosis were enrolled and divided into three groups: group 1 (n=24) was managed with only supportive care, group 2 (n=25) received systemic combination chemotherapy and group 3 (n=52) received intra-arterial infusion chemotherapy with 5-fluorouracil+cisplatin via implanted chemoport.: One-year survival rates were 0, 4, 21% and median survivals were 2, 4, 6 months in groups 1, 2, 3, respectively (p=0.003). When we divide group 3 patients into long-term (more than 8 months) or short-term survivors, long-term survivor had significantly low level of serum AST (p=0.032) and alkaline phosphatase (p=0.033). Especially, all female patients (n=9) survived more than 8 months (p=0.000). Other favorable prognostic factors for survival were cirrhosis of Child-Pugh class A (p=0.003), only one major branch involvement of the portal vein by tumor (p=0.005), presence of enhancement of tumor portion in arterial phase of CT scan (p=0.044), presence of enhancement of non-tumor portion in portal phase of CT scan (p=0.029).: Intra-arterial infusion chemotherapy achieved favorable results in advanced HCC with portal vein thrombosis and showed better survival in selected patients.
Therapeutic DNA cancer vaccines can stimulate specific immune responses against cancer antigens but often induce suboptimal therapeutic responses. Here, we demonstrate that a manganese-doped silica nanoparticle STING agonist (MSNA) enhances the immune response of plasmid DNA vaccines, promoting the activation and migration of distinct subsets of dendritic cell (DC) and improving antitumor immunity in three animal models. MSNA coadministered with an α-fetoprotein (AFP) encoded plasmid DNA (AFP-DNA) elicited significantly higher AFP-specific CD8 T cell responses than free AFP-DNA. Animals immunized with MSNA-AFP-DNA remained tumor-free in an AFP expressing hepatocellular carcinoma challenge model. MSNA combined with a DNA plasmid encoding the human papillomavirus type 16 oncoproteins E6 and E7 induced potent E7-specific CD8 T cell responses, preventing the growth of E7-expressing solid TC-1 tumors and promoting the shrinkage of E7-expressing skin grafts. These findings together demonstrate that coadministration of MSNA can improve the efficacy of therapeutic DNA vaccines targeting cancer-specific antigens.
// Xinxing Li 1, * , Weijun Wang 1, * , Canping Ruan 1, * , Yi Wang 1, * , Haolu Wang 2 , Xiaowen Liang 2 , Yanping Sun 1 and Zhiqian Hu 1 1 Department of General Surgery, Changzheng Hospital, The Second Military Medical University, Shanghai, 200003, China 2 Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia * These authors have contributed equally to this work Correspondence to: Xiaowen Liang, email: x.liang@uq.edu.au Yanping Sun, email: sunyanping2003@163.com Zhiqian Hu, email: huzhiq163@163.com Keywords: gastric cancer, distant metastasis, age, survival Received: December 08, 2016 Accepted: August 28, 2017 Published: September 28, 2017 ABSTRACT The age-specific impact on the survival of gastric cancer patients with distant metastasis is still unclear. In this study, we identified 11, 299 gastric cancer patients with distant metastasis between 2004 and 2013 from Surveillance, Epidemiology, and End Results population-based dataset. Patients were divided into young (≤60) and elderly groups (>60). Kaplan–Meier methods and multivariable Cox regression were used for the analysis of long-term survival outcomes and risk factors. There were significant differences between the two groups in terms of race, primary site, grade, histologic type, surgery, marital status and clinical T stage (P<0.05). The 1- and 3-year cancer specific survival rates were 29.0% and 6.2% in young group and 22.8% and 4.8% in elderly group in both univariate (X 2 =116.430, P<0.001) and multivariate analysis (P<0.001). Young patients had significantly better 1- and 3-year cancer specific survival than elderly patients in each T stage. Age was further validated as an independent survival factor in all T stages (T1, T2, T3, T4 and T X , P<0.05). In conclusion, age was an independent prognostic factor for gastric cancer patients with distant metastasis.
Abstract Oxidative stress reflects an imbalance between reactive oxygen species (ROS) and antioxidants, which has been reported as an early unifying event in the development and progression of various diseases and as a direct and mechanistic indicator of treatment response. However, highly reactive and short-lived nature of ROS and antioxidant limited conventional detection agents, which are influenced by many interfering factors. Here, we present a two-photon sensing platform for in vivo dual imaging of oxidative stress at the single cell-level resolution. This sensing platform consists of three probes, which combine the turn-on fluorescent transition-metal complex with different specific responsive groups for glutathione (GSH), hydrogen peroxide (H 2 O 2 ) and hypochlorous acid (HOCl). By combining fluorescence intensity imaging and fluorescence lifetime imaging, these probes totally remove any possibility of crosstalk from in vivo environmental or instrumental factors, and enable accurate localization and measurement of the changes in ROS and GSH within the liver. This precedes changes in conventional biochemical and histological assessments in two distinct experimental murine models of liver injury. The ability to monitor real-time cellular oxidative stress with dual-modality imaging has significant implications for high-accurate, spatially configured and quantitative assessment of metabolic status and drug response.
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