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Endothelial cells actively maintain an anti-thrombotic environment; loss of this protective function may lead to thrombosis and systemic coagulopathy. The transcription factor ERG is essential to maintain endothelial homeostasis. Here, we show that inducible endothelial ERG deletion (ErgiEC-KO) in mice is associated with spontaneous thrombosis, hemorrhages and systemic coagulopathy. We find that ERG drives transcription of the anticoagulant thrombomodulin (TM), as shown by reporter assays and chromatin immunoprecipitation. TM expression is regulated by shear stress (SS) via Krüppel-like factor 2 (KLF2). In vitro, ERG regulates TM expression under low SS conditions, by facilitating KLF2 binding to the TM promoter. However, ERG is dispensable for TM expression in high SS conditions. In ErgiEC-KO mice, TM expression is decreased in liver and lung microvasculature exposed to low SS but not in blood vessels exposed to high SS. Our study identifies an endogenous, vascular bed-specific anticoagulant pathway in microvasculature exposed to low SS. The endothelium actively maintains an anticoagulant surface through expression of thrombomodulin. Here, Peghaire et al. identify an anti-thrombotic pathway that controls thrombomodulin expression selectively in regions of low shear stress, via cooperation of the transcription factors ERG and KLF2. [ABSTRACT FROM AUTHOR]

Purpose: To assess the prognostic and predictive value of circulating tumor cells (CTCs) in metastatic colorectal cancer (mCRC) irrespective of detection level. Materials and methods: We evaluated the prognostic and predictive significance of CTC count at baseline and under treatment in 119 mCRC subjects and compared the standard cutoff (≥3 CTCs/7.5 mL to ≥1 CTCs/7.5 mL). Results: An overall comparison was made between patients with 0, 1-2 and ≥3 CTC (median PFS 8, 4 and 5 months, respectively). Two poor prognostic groups were found, including patients with ≥1 CTCs before and during treatment and patients with 0 CTC at baseline who converted to ≥1 CTCs ( p = 0.014). Conclusions: The presence of at least 1 CTC at baseline count is predictive for poor prognosis in mCRC patients. Patients with 1-2 CTC should be switched from the favorable prognostic group-conventionally defined by the presence of <3 CTC-to the unfavorable, deserving a more careful monitoring. [ABSTRACT FROM AUTHOR]

Brain death (BD), a non-immunological factor of renal injury, triggers an inflammatory process causing pathological signs of cell death in the kidney, such as necrosis and apoptosis. Kidneys from brain dead donors show lower success rates than kidneys from living donors and one strategy to improve transplantation outcome is to precondition the donors. For the first time, anti-rat thymoglobulin (rATG) was administered in an experimental brain death animal model to evaluate if it could ameliorate histopathological damage and improve organ function. Animals were divided into three groups: V ( n = 5) ventilated for 2 h; BD ( n = 5) brain death and ventilated for 2 h; and BD+rATG ( n = 5) brain death, ventilated for 2 h, rATG was administered during brain death (10 mg/kg). We observed lower creatinine levels in treatment groups (means): V, 0·88 ± 0·22 mg/dl; BD, 1·37 ± 0·07 mg/dl; and BD+rATG, 0·64 ± 0·02 mg/dl (BD versus BD+rATG, P < 0·001). In the BD group there appeared to be a marked increase of ATN, whereas ATN was decreased significantly in the rATG group (V, 2·25 ± 0·5 versus BD, 4·75 ± 0·5, P < 0·01; BD+rATG, 2·75 ± 0·5 versus BD 4·75 ± 0·5 P < 0·01). Gene expression was evaluated with reverse transcription-polymerase chain reaction; tumour necrosis factor (TNF)-α, interleukin (IL)-6, C3, CD86 showed no significant difference between groups. Increased IL-10 and decreased CCL2 in BD+rATG compared to BD (both cases P < 0·01). Myeloperoxidase was increased significantly after the brain death setting (V: 32 ± 7·5 versus BD: 129 ± 18). Findings suggest that rATG administered to potential donors may ameliorate renal damage caused by BD. These findings could contribute in the search for specific cytoprotective interventions to improve the quality and viability of transplanted organs. [ABSTRACT FROM AUTHOR]

Summary Reperfusion injury remains one of the major problems in transplantation. Repair from ischaemic acute renal failure (ARF) involves stimulation of tubular epithelial cell proliferation. The aim of this exploratory study was to evaluate the effects of preconditioning donor animals with rapamycin and tacrolimus to prevent ischaemia-reperfusion (I/R) injury. Twelve hours before nephrectomy, the donor animals received immunosuppressive drugs. The animals were divided into four groups, as follows: group 1 control: no treatment; group 2: rapamycin (2 mg/kg); group 3 FK506 (0, 3 mg/kg); and group 4: FK506 (0, 3 mg/kg) plus rapamycin (2 mg/kg). The left kidney was removed and after 3 h of cold ischaemia, the graft was transplanted. Twenty-four hours after transplant, the kidney was recovered for histological analysis and cytokine expression. Preconditioning treatment with rapamycin or tacrolimus significantly reduced blood urea nitrogen and creatinine compared with control [blood urea nitrogen (BUN): P < 0·001 versus control and creatinine: P < 0·001 versus control]. A further decrease was observed when rapamycin was combined with tacrolimus. Acute tubular necrosis was decreased significantly in donors treated with immunosuppressants compared with the control group ( P < 0·001 versus control). Moreover, the number of apoptotic nuclei in the control group was higher compared with the treated groups ( P < 0·001 versus control). Surprisingly, only rapamycin preconditioning treatment increased anti-apoptotic Bcl2 levels ( P < 0·001). Finally, inflammatory cytokines, such as tumour necrosis factor (TNF)-α and interleukin (IL)-6, showed lower levels in the graft of those animals that had been pretreated with rapamycin or tacrolimus. This exploratory study demonstrates that preconditioning donor animals with rapamycin or tacrolimus improves clinical outcomes and reduce necrosis and apoptosis in kidney I/R injury. [ABSTRACT FROM AUTHOR]

Extracorporeal dialysis was first performed in 1943 and has become a routine for End Stage Renal Patients from the early sixties. In the last 30 years researchers have focused on biocompatibility of artificial materials and optimisation of removal of uremic toxins by the membrane as in the long term treatment many complications like amylodosis heart and bone lesions, accelerated amyloidosis and immune system failure can occur. From this point of view high flux dialytic membranes are currently considered more biocompatible therefore being able to prevent such diseases. [ABSTRACT FROM AUTHOR]