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Full-Text Articles in Molecular Biology

Tumor Interferon Signaling Initiates And Sustains A Multigenic Resistance Program To Immune Checkpoint Blockade, Joseph Lawrence Benci Jan 2017

Tumor Interferon Signaling Initiates And Sustains A Multigenic Resistance Program To Immune Checkpoint Blockade, Joseph Lawrence Benci

Publicly Accessible Penn Dissertations

Therapeutic blockade of the CTLA4 and/or PD1 immune checkpoint pathways has resulted in significant anti-tumor responses in broad variety of cancer types, but resistance is common. Using mouse models of metastatic melanoma and breast cancer in combination with CRISPR/Cas9 to selectively delete genes in our tumor cells, we demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB), and to combinations such as radiation plus anti-CTLA4. Furthermore, we show that this interferon driven resistance mechanism primarily occurs in ICB resistant tumors and not in ICB responsive tumors. Persistent type II interferon signaling allows ...


Single Human Cells Use Transcriptional Mechanisms To Compensate For Differences In Cell Size And Dna Content, Olivia Padovan-Merhar Jan 2015

Single Human Cells Use Transcriptional Mechanisms To Compensate For Differences In Cell Size And Dna Content, Olivia Padovan-Merhar

Publicly Accessible Penn Dissertations

Human cells are dynamic: they grow, replicate their genetic information (DNA), and divide. Clonal populations of cells can display marked heterogeneity in size, leading to significant variability in the ratio of DNA to cellular volume. Despite this variability, cells must maintain a constant concentration of RNA and protein, produced from DNA, to ensure proper functionality. How do larger cells produce more output from the same amount of DNA? How do cells that have replicated their DNA prior to cellular division produce the same output as before? Using RNA fluorescence in situ hybridization (RNA FISH), we visualize and count individual RNA ...


Inducible Protein Dimerization: New Tools And Applications To Understanding The Mitotic Checkpoint, Edward Raymond Ballister Jan 2014

Inducible Protein Dimerization: New Tools And Applications To Understanding The Mitotic Checkpoint, Edward Raymond Ballister

Publicly Accessible Penn Dissertations

Cellular processes such as growth, migration, signaling and cell division require choreographed interactions between dozens or hundreds of proteins carefully organized in time and space. In order to test hypotheses about complex cellular functions, it is desirable to experimentally perturb the interactions of individual proteins that perform these functions with a level of spatial and temporal control commensurate with the time and space scales over which the system is naturally organized. Inducible protein dimerization offers the ability to experimentally control protein-protein interactions. Inducible dimerization can be used to test the immediate effects of dimerizing two proteins, or it can be ...