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1.  Outcome stagnation of liver transplantation for primary sclerosing cholangitis in the Model for End-Stage Liver Disease era 
Langenbeck's Archives of Surgery  2014;399(8):1021-1029.
Survival after liver transplantation (LTX) has decreased in Germany since the implementation of Model for end-stage liver disease (MELD)-based liver allocation. Primary sclerosing cholangitis (PSC) is known for its otherwise excellent outcome after LTX. The influence of MELD-based liver allocation and subsequent allocation policy alterations on the outcome of LTX for PSC is analyzed.
This is a retrospective observational study including 126 consecutive patients treated with LTX for PSC between January 1, 1999 and August 31, 2012. The PSC cohort was further compared to all other indications for LTX in the study period (n = 1420) with a mean follow-up of 7.9 years (SD 3.2). Multivariate risk-adjusted analyses were performed. Alterations of allocation policy have been taken into account systematically.
Transplant recipients suffering from PSC are significantly younger (p < 0.001), can be discharged earlier (p = 0.018), and have lower 3-month mortality than patients with other indications (p = 0.044). The observed time on the waiting list is significantly longer for patients with PSC (p < 0.001), and there is a trend toward lower match MELD points in the PSC cohort (p = 0.052). No improvement in means of short-term mortality could be shown in relation to alterations of allocation policy within the MELD era (p = 0.375). Survival rates of the pre-MELD era did not differ significantly from those of the MELD era (p = 0.097) in multivariate risk-adjusted analysis. Patients in the MELD era suffered pre-transplant significantly more frequently from dominant bile duct stenosis (p = 0.071, p = 0.059, p = 0.048, respectively; chi2).
Progress is stagnating in LTX for PSC. Current liver allocation for PSC patients should be reconsidered.
PMCID: PMC4232743  PMID: 24888532
MELD-based allocation; Cholangiocarcinoma; Outcome; Survival; Autoimmune liver disease; Multivariate analysis
2.  Inhibition of Autophagic Flux by Salinomycin Results in Anti-Cancer Effect in Hepatocellular Carcinoma Cells 
PLoS ONE  2014;9(5):e95970.
Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC) cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH) likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0–10 µM), comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS) formation. Impact on apoptosis induction and cell function of PHH was analyzed.
Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis.
PMCID: PMC4015957  PMID: 24816744
3.  Impact of Salinomycin on human cholangiocarcinoma: induction of apoptosis and impairment of tumor cell proliferation in vitro 
BMC Cancer  2012;12:466.
Cholangiocarcinoma (CC) is a primary liver cancer with increasing incidence worldwide. Despite all efforts made in past years, prognosis remains to be poor. At least in part, this might be explained by a pronounced resistance of CC cells to undergo apoptosis. Thus, new therapeutic strategies are imperatively required. In this study we investigated the effect of Salinomycin, a polyether ionophore antibiotic, on CC cells as an appropriate agent to treat CC. Salinomycin was quite recently identified to induce apoptosis in cancer stem cells and to overcome apoptosis-resistance in several leukemia-cells and other cancer cell lines of different origin.
To delineate the effects of Salinomycin on CC, we established an in vitro cell culture model using three different human CC cell lines. After treatment apoptosis as well as migration and proliferation behavior was assessed and additional cell cycle analyses were performed by flowcytometry.
By demonstrating Annexin V and TUNEL positivity of human CC cells, we provide evidence that Salinomycin reveals the capacity to break apoptosis-resistance in CC cells. Furthermore, we are able to demonstrate that the non-apoptotic cell fraction is characterized by sustainable impaired migration and proliferation. Cell cycle analyses revealed G2-phase accumulation of human CC cells after treatment with Salinomycin. Even though apoptosis is induced in two of three cell lines of CC cells, one cell line remained unaffected in regard of apoptosis but revealed as the other CC cells decreased proliferation and migration.
In this study, we are able to demonstrate that Salinomycin is an effective agent against previously resistant CC cells and might be a potential candidate for the treatment of CC in the future.
PMCID: PMC3487825  PMID: 23057720
Salinomycin; Cholangiocarcinoma; Apoptosis; Tumor cell migration; Cell cycle

Results 1-3 (3)