FTY720 Suppresses Liver Tumor Metastasis by Reducing the Population of Circulating Endothelial Progenitor Cells

Background: Surgical procedures such as liver resection and liver transplantation are the first-line treatments for hepatocellular carcinoma (HCC) patients. However, the high incidence of tumor recurrence and metastasis after liver surgery remains a major problem. Recent studies have shown that hepatic ischemia-reperfusion (I/R) injury and endothelial progenitor cells (EPCs) contribute to tumor growth and metastasis. We aim to investigate the mechanism of FTY720, which was originally applied as an immunomodulator, on suppression of liver tumor metastasis after liver resection and partial hepatic I/R injury. Methodology/Principal Findings: An orthotopic liver tumor model in Buffalo rat was established using the hepatocellular carcinoma cell line McA-RH7777. Two weeks after orthotopic liver tumor implantation, the rats underwent liver resection for tumor-bearing lobe and partial hepatic I/R injury. FTY720 (2 mg/kg) was administered through the inferior caval vein before and after I/R injury. Blood samples were taken at days 0, 1, 3, 7, 14, 21 and 28 for detection of circulating EPCs (CD133+CD34+). Our results showed that intrahepatic and lung metastases were significantly inhibited together with less tumor angiogenesis by FTY720 treatment. The number of circulating EPCs was also significantly decreased by FTY720 treatment from day 7 to day 28. Hepatic gene expressions of CXCL10, VEGF, CXCR3, CXCR4 induced by hepatic I/R injury were down-regulated in the treatment group. Conclusions/Significance: FTY720 suppressed liver tumor metastasis after liver resection marred by hepatic I/R injury in a rat liver tumor model by attenuating hepatic I/R injury and reducing circulating EPCs. © 2012 Li et al.published_or_final_versio

Guided self-organization and cortical plate formation in human brain organoids.

Three-dimensional cell culture models have either relied on the self-organizing properties of mammalian cells or used bioengineered constructs to arrange cells in an organ-like configuration. While self-organizing organoids excel at recapitulating early developmental events, bioengineered constructs reproducibly generate desired tissue architectures. Here, we combine these two approaches to reproducibly generate human forebrain tissue while maintaining its self-organizing capacity. We use poly(lactide-co-glycolide) copolymer (PLGA) fiber microfilaments as a floating scaffold to generate elongated embryoid bodies. Microfilament-engineered cerebral organoids (enCORs) display enhanced neuroectoderm formation and improved cortical development. Furthermore, reconstitution of the basement membrane leads to characteristic cortical tissue architecture, including formation of a polarized cortical plate and radial units. Thus, enCORs model the distinctive radial organization of the cerebral cortex and allow for the study of neuronal migration. Our data demonstrate that combining 3D cell culture with bioengineering can increase reproducibility and improve tissue architecture

A critical appraisal of intravenous fluids: from the physiological basis to clinical evidence

Fluid management has been a vital part of routine clinical care for more than 180 years. The increasing number of available fluids has generated controversy about the optimal choice of resuscitation fluid. In this review, we provide a critical overview of the different fluids available, their composition, the relevant physiology as well as the published evidence on clinical outcomes to guide their use. Commonly used infusion fluids include semisynthetic colloids and crystalloids; the latter comprises both normal saline (NaCl 0.9%) and themore chloride-restricted 'balanced' crystalloids. Despite their significantly greater intravascular persistence, semisynthetic colloids have an importantly adverse safety profile and are associated with greater incidence of renal failure and increased mortality; their use should be restricted. To date, evidence for clinical benefits associated with albumin solutions is generally lacking; its merits in specific clinical situations are the subject of further investigation. Infusion of normal saline, with its supraphysiological chloride content, is associated with higher serum chloride concentrations and metabolic acidosis, as well as renal vasoconstriction in animal and human models. Infusion of 'balanced' crystalloids is not linked to such changes. Although data on clinical outcomes associated with crystalloid infusion are heterogeneous, advantages of balanced salt solutions might include a lower need of blood products, and lower incidence of renal replacement therapy, hyperkalaemia and postoperative infections. Taken together, a critical appraisal of the data suggests that balanced salt solutions deserve consideration as infusates of first choice

Vitamin K antagonist use and renal function in pre-dialysis patients

Pauline WM Voskamp,1 Friedo W Dekker,1 Maarten B Rookmaaker,2 Marianne C Verhaar,2 Willem Jan W Bos,3 Merel van Diepen,1 Gurbey Ocak2 1Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 2Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands; 3Department of Nephrology, Sint Antonius Hospital, Nieuwegein, the Netherlands Purpose: A post hoc analysis of a recent trial on direct oral anticoagulants versus vitamin K antagonists showed that amongst patients with mildly decreased kidney function, use of vitamin K antagonists was associated with a greater decline in renal function than use of direct oral anticoagulants. Whether these vitamin K antagonist effects are the same in pre-dialysis patients is unknown. Therefore, the aim of this study was to investigate the association between vitamin K antagonist use and the rate of renal function decline and time until start of dialysis in incident pre-dialysis patients.Methods: Data from 984 patients from the PREdialysis PAtient REcord study, a multicenter follow-up study of patients with chronic kidney disease who started pre-dialysis care in the Netherlands (1999–2011), were analyzed. Of these patients, 101 used a vitamin K antagonist. Linear mixed models were used to compare renal function decline between vitamin K antagonist users and non-users. Cox proportional hazards models were used to estimate the HR with 95% CI for starting dialysis.Results: Vitamin K antagonist use was associated with an extra change in renal function of –0.09 (95% CI –1.32 to 1.13) mL/min/1.73 m2 per year after adjustment for confounding. The adjusted HR for the start of dialysis was 1.20 (95% CI 0.85 to 1.69) in vitamin K antagonist users, compared to non-users. Conclusion: In incident pre-dialysis patients, the use of vitamin K antagonists was not associated with an accelerated kidney function decline or an earlier start of dialysis compared to non-use. The lack of knowledge on the indication for vitamin K antagonist use could lead to confounding by indication. Keywords: coumarins, epidemiology, chronic kidney disease, glomerular filtration rat

The role of microvesicles in tissue repair

Microvesicles (MVs) are released by almost all cells in resting and activated conditions. First described several years ago, it is only recently that their mechanisms of action are being elucidated, and their potential role in health and disease is drawing increasing attention. The main function of MVs is signaling through specific interactions with target cells and the transferring of gene products. Gaining further insights into the molecular specificity of MVs has allowed identification of the cellular source and may provide new diagnostic tools in the future. Indeed, an increasing body of evidence indicates that MVs are capable of mediating tissue repair in models of acute kidney and liver injury. In this review, we will discuss the mechanisms through which MVs from stem cells may act on target cells and may modify the response to injury. Furthermore, MVs from inflammatory cells are suspected to be involved in various diseases, such as cardiovascular and renal diseases, pathological pregnancy, tumors and sepsis. MVs are no doubt also involved in modulating immunity, and future studies will clarify their functional role in negatively modulating the cell response. Their role in physiological and pathological processes is increasingly appreciated. Depending on the cell source and the condition, MVs may be either beneficial or detrimental to the host. The recognition of their pathogenetic role may suggest new approaches to future therapies