Atanasova, Elena

Abstract BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive pulmonary disease characterized by aberrant tissue remodeling, formation of scar tissue within the lungs and continuous loss of lung function. The areas of fibrosis seen in lungs of IPF patients share many features with normal aging lung with cellular senescence being one. The contribution of the immune system to the etiology of IPF remains poorly understood. Evidence obtained from animal models and human studies suggests that innate and adaptive immune processes can orchestrate existing fibrotic responses. Currently, there is only modestly effective pharmacotherapy for IPF. Mesenchymal stem cells (MSCs)-based therapies have emerged as a potential option treatment of IPF. This study explores the possibility of using autologous MSCs as an IPF therapy and present an attempt to determine if the disease occurring in the lungs can be reflected on peripheral blood immune status. MethodsComprehensive characterization of autologous adipose derived MSCs (aMSCs) from five IPF patients and five age and gender matched Healthy Controls (HC) was done using flow cytometry, Droplet Digital PCR (ddPCR), Multiplex Luminex xMAP technology and confocal microscopy. For assessing the self renewal capacity and osteogenic differentiation IncuCyte Live Cell Imaging technology was used. Multi-parameter quantitative flow cytometry of un-manipulated whole blood of another group of 15 IPF patients and 87 (30 age and gender matched) HC was used to analyze 110 peripheral phenotypes.ResultsThere are no differences between autologous aMSCs from IPF patients and HC in their stem cell properties, self renewal capacity, plasticity for osteogenic differentiation, secretome content, cell cycle inhibitor marker levels and mitochondrial health. IPF patients had altered peripheral blood immunophenotype including reduced B cells subsets, increased T cell subsets, and increased granulocytes among others demonstrating clear and significant differences.ConclusionsOur results indicate that there is no difference in aMSCs properties from IPF patients and HC, suggesting that autologous aMSCs may be an acceptable option for IPF therapy.Characterization of peripheral immune phenotype may be a valuable indicator for successful therapy, and for potentially staging the disease.

Abstract Antibody-directed chemotherapy (ADC) offers an advantage over conventional chemotherapy because it provides antibody-directed targeting, with resultant improvement in therapeutic efficacy and reduced toxicity. Despite extensive research, with notable exceptions, broad clinical application of ADC remains elusive; major hurdles include the instability of antibody–chemotherapy linkers and reduced tumor toxicity of the chemotherapy when bound to the antibody. To address these challenges, we have developed a platform technology that utilizes the nab-paclitaxel formulation of paclitaxel, Abraxane, in which hydrophobic paclitaxel is suspended in 130-nm albumin nanoparticles and thus made water-soluble. We have developed a method to noncovalently coat the Abraxane nanoparticle with recombinant mAbs (anti-VEGF, bevacizumab) and guide Abraxane delivery into tumors in a preclinical model of human A375 melanoma. Here, we define the binding characteristics of bevacizumab and Abraxane, demonstrate that the chemotherapy agent retains its cytotoxic effect, while the antibody maintains the ability to bind its ligand when the two are present in a single nanoparticle (AB160), and show that the nanoparticle yields improved antitumor efficacy in a preclinical human melanoma xenograft model. Further data suggest that numerous therapeutic monoclonal IgG1 antibodies may be utilized in this platform, which has implications for many solid and hematologic malignancies. Cancer Res; 76(13); 3954–64. ©2016 AACR.

Epigenetic inheritance of heterochromatin structure is an important cellular process whose mechanism remains elusive. In this article, we describe the identification of nine enhancers of the silencing defect of a Saccharomyces cerevisiae -PCNA mutant by screening a library of ≈4,700 viable yeast deletion mutants. Of the nine mutants identified, six ( hir1 , hir3 , sas2 , sas4 , sas5 , and sir1 ) were previously known to reduce silencing synergistically with a mutation in Cac1p, the large subunit of chromatin assembly factor 1 (CAF-1). The predicted gene products that are affected in three other mutants ( nam7 , msh2 , and rtt106 ) have not been implicated previously in silencing. Characterization of the rtt106 Δ allele revealed that it synergistically reduced heterochromatin silencing when combined with a mutation in Cac1p but not with a mutation in Asf1p (a histone H3 and H4 chaperone). Moreover, Rtt106p interacted with histones H3 and H4 both in vitro and in vivo , and it displayed a nucleosome assembly activity in vitro . Furthermore, Rtt106p interacts with CAF-1 physically through Cac1p. These biochemical and genetic data indicate that Rtt106p is a previously uncharacterized histone chaperone connecting S phase to epigenetic inheritance.