In this task, you are given an abstract of article. Your task is to generate title for this article. Preferred titles are under thirty words.

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Mesenchymal stem cells (MSCs) display substantial cell-to-cell variation. This heterogeneity manifests among donors, among tissue sources, and within cell populations. Such pervasive variability complicates the use of MSCs in regenerative applications and may limit their therapeutic efficacy. Most conventional assays measure MSC properties in bulk and, as a consequence, mask this cell-to-cell variation. Recent studies have identified extensive variability amongst and within clonal MSC populations, in dimensions including functional differentiation capacity, molecular state (e.g. epigenetic, transcriptomic, and proteomic status), and biophysical properties. While the origins of these variations remain to be elucidated, potential mechanisms include in vivo micro-anatomical heterogeneity, epigenetic bistability, and transcriptional fluctuations. Emerging tools for single cell analysis of MSC gene and protein expression may yield further insight into the mechanisms and implications of single cell variation amongst these cells, and ultimately improve the clinical utility of MSCs in tissue engineering and regenerative medicine applications. This review outlines the dimensions across which MSC heterogeneity is present, defines some of the known mechanisms that govern this heterogeneity, and highlights emerging technologies that may further refine our understanding and improve our clinical application of this unique cell type.

Ex Output:
On the origin and impact of mesenchymal stem cell heterogeneity: new insights and emerging tools for single cell analysis.

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BACKGROUND In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM.
PATIENTS AND METHODS Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points.
RESULTS Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade 3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade 3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths.
CONCLUSION HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. EUDRACT NUMBER AND CLINICALTRIALSGOV IDENTIFIER 2004-002245-12 and NCT00110123.

Ex Output:
Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial.

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The expression of melanoma-associated antigens (MAA) being limited to normal melanocytes and melanomas, MAAs are ideal targets for immunotherapy and melanoma vaccines. As MAAs are derived from self, immune responses to these may be limited by thymic tolerance. The extent to which self-tolerance prevents efficient immune responses to MAAs remains unknown. The autoimmune regulator (AIRE) controls the expression of tissue-specific self-antigens in thymic epithelial cells (TECs). The level of antigens expressed in the TECs determines the fate of auto-reactive thymocytes. Deficiency in AIRE leads in both humans (APECED patients) and mice to enlarged autoreactive immune repertoires. Here we show increased IgG levels to melanoma cells in APECED patients correlating with autoimmune skin features. Similarly, the enlarged T cell repertoire in AIRE(-/-) mice enables them to mount anti-MAA and anti-melanoma responses as shown by increased anti-melanoma antibodies, and enhanced CD4(+) and MAA-specific CD8(+) T cell responses after melanoma challenge. We show that thymic expression of gp100 is under the control of AIRE, leading to increased gp100-specific CD8(+) T cell frequencies in AIRE(-/-) mice. TRP-2 (tyrosinase-related protein), on the other hand, is absent from TECs and consequently TRP-2 specific CD8(+) T cells were found in both AIRE(-/-) and AIRE(+/+) mice. This study emphasizes the importance of investigating thymic expression of self-antigens prior to their inclusion in vaccination and immunotherapy strategies.

Ex Output:
The Immune Response to Melanoma Is Limited by Thymic Selection of Self-Antigens