With sumoylation of Ndc10 being functionally relevant. Sumoylation-deficient Ndc10 fails to localize to the mitotic spindle, resulting in defective chromosome segregation. The short defined point centromeres to which Ndc10 binds are unique to the Saccharomycetaceae family of budding yeast, and were recently proposed to have arisen by TWS119 601514-19-6 replacement of a typical epigenetic fungal centromere with an ancestral 2 mm plasmid-derived partitioning system. While rapid evolution may have obscured sequence homology between the 2 mm plasmid and chromosomal segregation proteins, it is tempting to speculate that post-translational modification of segregation proteins with SUMO might be a conserved process, essential for their common function. The yeast 2 mm plasmid is not the only parasitic DNA element to exploit the host cell SUMO pathway for its maintenance. Many viral proteins involved in maintenance of the episomes that encode them are SUMO-modified. Members of the human papillomavirus E2 family of proteins are dependent on sumoylation for their ability to tether viral genomes to host chromosomes to ensure faithful segregation. Host sumoylation has therefore frequently been exploited to ensure maintenance of parasitic genomes in eukaryotic cells, and here 
we have presented evidence that suggests the yeast 2 mm plasmid may also co-opt this essential cellular process to ensure its efficient segregation during host cell division. Adoptive transfer of ex vivo expanded autologous tumorinfiltrating lymphocytes together followed by one to two cycles of high-dose IL-2 therapy has emerged in multiple Phase II clinical trials to be one of the most powerful therapies for unresectable metastatic melanoma. Durable clinical response rates of up to 50% have been consistently reported using a current protocol consisting of a lymphodepleting preconditioning regimen using cyclophosphamide and fludaribine followed by expanded TIL infusion and IL-2. Our group at MD Anderson Cancer Center has recently completed a study on 31 metastatic patients that have failed multiple first- and second- line therapies using this regimen and reported a 48% clinical response rate. Most responding patients have had progression-free survival times after treatment of.15 LY2109761 months, which is longer than those achieved using other therapies, including targeted therapies with MAPK inhibitors. Although other forms of T-cell therapy have become available, TIL therapy has still remained the superior form of therapy for melanoma because it targets many tumor antigens recognized by a more heterogenous population of T cells rather than a single antigen that can be lost due to the high mutation rates in melanomas. The current method to generate the final TIL product for infusion uses a “rapid expansion protocol” consisting of taking TIL initially expanded from tumor fragments with IL-2 alone for 3�C4 weeks and activating them with anti-CD3 in the presence of a large excess of irradiated PBMC feeder cells. The cells are then expanded for 2 weeks by feeding with culture medium and IL-2. The feeder cells presumably provide a source of Fc receptors for anti-CD3 cross-linking as well as some limited growth factors, anti-oxidants, and co-stimulatory factors for TIL expansion.