Polymeric micelles, self-assembling nano-constructs of amphiphilic copolymers, are widely considered as convenient nano-carriers for a variety of applications, such as diagnostic imaging, and drug and gene delivery. They have demonstrated a variety of favorable properties including biocompatibility, longevity, high stability in vitro and in vivo, capacity to effectively solubilize a variety of poorly soluble drugs, changing the release profile of the incorporated pharmaceutical agents, and the ability to accumulate in the target zone based on the enhanced permeability and retention effect. Moreover, additional functions can be imparted to the micelle-based delivery systems by engineering their surface for specific applications. Various targeting ligands can be attached for cell or intracellular accumulation at a site of interest. Also, the chelation or incorporation of imaging moieties into the micelle structure enables in vivo biodistribution studies. Moreover, pH-, thermo-, ultrasound-, enzyme- and light-sensitive block-copolymers allow for controlled micelle dissociation and triggered drug release in response to the pathological environment-specific stimuli and/or externally applied signals. The combination of these approaches can further improve specificity and efficacy of micelle-based drug delivery to promote the development of smart multifunctional micelles.
© 2015 Wiley Periodicals, Inc.

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Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) secrete various beneficial molecules, which have anti-apoptotic activity and cell proliferation. However, the effect of hUCB-MSCs in melanogenesis is largely unclear. In this study, we show that conditioned media (CM) derived from hUCB-MSCs inhibit melanogenesis by regulating microphthalmia-associated transcription factor (MITF) expression via the ERK signalling pathway. Treatment of hUCB-MSC-CM strongly inhibited the alpha-melanocyte stimulating hormone-induced hyperpigmentation in melanoma cells as well as melanocytes. Treatment of hUCB-MSC-CM induced ERK1/2 activation in melanocytes. In addition, inhibition of ERK1/2 suppressed the anti-pigmentation activity of the hUCB-MSC-CM in melanocytes and in vitro artificial skin models. We also found that the expression of MITF was appreciably diminished while expression of phosphorylated MITF, which leads to its proteasomal degradation, was increased in cells treated with hUCB-MSC-CM. These results suggested that hUCB-MSC-CM significantly suppresses melanin synthesis via MITF degradation by the ERK pathway activation.

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The degeneration of substantia nigra (SN) dopamine (DA) neurons in sporadic Parkinson׳s disease (PD) is characterized by disturbed gene expression networks. Micro(mi)RNAs are post-transcriptional regulators of gene expression and we recently provided evidence that these molecules may play a functional role in the pathogenesis of PD. Here, we document a comprehensive analysis of miRNAs in SN DA neurons and PD, including sex differences. Our data show that miRNAs are dysregulated in disease-affected neurons and differentially expressed between male and female samples with a trend of more up-regulated miRNAs in males and more down-regulated miRNAs in females. Unbiased Ingenuity Pathway Analysis (IPA) revealed a network of miRNA/target-gene associations that is consistent with dysfunctional gene and signaling pathways in PD pathology. Our study provides evidence for a general association of miRNAs with the cellular function and identity of SN DA neurons, and with deregulated gene expression networks and signaling pathways related to PD pathogenesis that may be sex-specific.
Copyright © 2015 Elsevier B.V. All rights reserved.

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Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multi-organ failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identified from the CIBMTR clinical database; 3.2% met criteria for VOD and 1.2% met criteria for severe VOD. Patients with a diagnosis of VOD as reported to the CIBMTR by their transplanting centers, who had no prior history of cirrhosis, and who had a maximum total bilirubin >2.0mg/dl by day +100 post-HCT were selected for study. Severe VOD was defined as VOD occurring in the setting of renal impairment requiring dialysis or any non-infectious pulmonary abnormality. Patients with severe VOD were divided into two groups for analysis: those treated with defibrotide (n=41) and those not treated with defibrotide (n=55). Patients in the non-defibrotide group were older, were more likely to be male, were more likely to have a history of previous fungal infection, and had a higher proportion of clinically significant pre-existing disease or organ impairment. Survival at day +100 was 39% (95% CI: 24.8-54.3%) in patients receiving defibrotide and 30.9% (95% CI: 19.5% – 43.6%) in those not receiving defibrotide. Resolution of VOD at day +100 was 51% in the defibrotide group, and 29% in the non-defibrotide group (difference 22.1%, 95% CI: 2.6% – 42%). The results of our study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defibrotide is effective in the treatment of severe VOD.
Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

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To assess sirukumab, an anti-interleukin-6 monoclonal antibody, for treatment of active lupus nephritis (LN).
Patients with Class III or IV LN (renal biopsy within 14 months of randomization), persistent proteinuria (≥0.5 g/d) despite immunosuppression, and stable renin-angiotensin system blockade were randomized (5:1) to receive intravenous sirukumab 10 mg/kg (n=21) or placebo (n=4) every 4 weeks through week 24. The primary endpoint was percent reduction of proteinuria (measured as the protein/creatinine ratio in a 12-hour urine collection) from baseline to week 24.
Twenty-five patients were enrolled; 19 (76.0%) completed treatment through week 24, and 6 (24.0%) discontinued the study agent early, 5 due to adverse events. At week 24, the median percent change in proteinuria from baseline in sirukumab-treated patients was 0.0% (95% CI: -61.8, 39.6). In contrast, the 4 placebo patients showed a median percent increase in proteinuria of 43.3% at week 24. Of note, a subset of 5 sirukumab-treated patients had ≥50% improvement in their protein/creatinine ratio through week 28. In the sirukumab group, 47.6% of patients had ≥1 serious adverse event; most were infection-related. No deaths or malignancies occurred. No serious adverse events were observed in the four placebo-treated patients.
This proof-of-concept study did not demonstrate the anticipated efficacy or an acceptable safety profile following sirukumab treatment in this population of patients with active LN receiving concomitant immunosuppressive treatment. This article is protected by copyright. All rights reserved.
© 2016, American College of Rheumatology.

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