FIX latex errors
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@ -81,6 +81,9 @@
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palindromic repeats}
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palindromic repeats}
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\newacronym{mtt}{MTT}{3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide}
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\newacronym{mtt}{MTT}{3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide}
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\newacronym{bmi}{BMI}{body mass index}
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\newacronym{bmi}{BMI}{body mass index}
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\newacronym{a2b1}{A2B1}{integrin $\upalpha$1$\upbeta$1}
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\newacronym{a2b2}{A2B2}{integrin $\upalpha$1$\upbeta$2}
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\newacronym{til}{TIL}{tumor infiltrating lymphocytes}
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%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%
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%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%
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% SI units for uber nerds
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% SI units for uber nerds
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@ -1403,27 +1406,27 @@ subsets to be included in CAR T cell therapy given a disease state.
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% the signaling and why this might matter
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% the signaling and why this might matter
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There are several plausible explanations for the observed phenotypic differences
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There are several plausible explanations for the observed phenotypic differences
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between beads and DMSs. First, the DMSs are composed of a collagen derivative
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between beads and DMSs. First, the DMSs are composed of a collagen derivative
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(gelatin); collagen has been shown to costimulate activated T cells via α1β1 and
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(gelatin); collagen has been shown to costimulate activated T cells via
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α2β1 integrins, leading to enhanced proliferation, increased IFNγ production,
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\gls{a2b1} and \gls{a2b2}, leading to enhanced proliferation, increased
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and upregulated CD25 (IL2Rα) surface expression8,10,11,41,42. Second, there is
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IFN$\upgamma$ production, and upregulated CD25 (IL2R$\upalpha$) surface
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evidence that providing a larger contact area for T cell activation provides
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expression8,10,11,41,42. Second, there is evidence that providing a larger
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greater stimulation16,43; the DMSs have a rougher interface than the 5 µm
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contact area for T cell activation provides greater stimulation16,43; the DMSs
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magnetic beads, and thus could facilitate these larger contact areas. Third, the
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have a rougher interface than the 5 µm magnetic beads, and thus could facilitate
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DMSs may allow the T cells to cluster more densely compared to beads, as
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these larger contact areas. Third, the DMSs may allow the T cells to cluster
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evidenced by the large clusters on the outside of the DMSs (Figure 1f) as well
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more densely compared to beads, as evidenced by the large clusters on the
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as the significant fraction of DMSs found within their interiors (Supplemental
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outside of the DMSs (Figure 1f) as well as the significant fraction of DMSs
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Figure 2a and b). This may alter the local cytokine environment and trigger
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found within their interiors (Supplemental Figure 2a and b). This may alter the
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different signaling pathways. Particularly, IL15 and IL21 are secreted by T
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local cytokine environment and trigger different signaling pathways.
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cells and known to drive memory phenotype44–46. We noted that the IL15 and IL21
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Particularly, IL15 and IL21 are secreted by T cells and known to drive memory
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concentration was higher in a majority of samples when comparing beads and DMSs
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phenotype44–46. We noted that the IL15 and IL21 concentration was higher in a
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across multiple timepoints (Supplemental Figure 18) in addition to many other
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majority of samples when comparing beads and DMSs across multiple timepoints
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cytokines. IL15 and IL21 are added exogenously to T cell cultures to enhance
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(Supplemental Figure 18) in addition to many other cytokines. IL15 and IL21 are
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memory frequency,45,47 and our data here suggest that the DMSs are better at
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added exogenously to T cell cultures to enhance memory frequency,45,47 and our
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naturally producing these cytokines and limiting this need. Furthermore, IL15
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data here suggest that the DMSs are better at naturally producing these
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unique signals in a trans manner in which IL15 is presented on IL15R to
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cytokines and limiting this need. Furthermore, IL15 unique signals in a trans
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neighboring cells48. The higher cell density in the DMS cultures would lead to
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manner in which IL15 is presented on IL15R to neighboring cells48. The higher
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more of these trans interactions, and therefore upregulate the IL15 pathway and
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cell density in the DMS cultures would lead to more of these trans interactions,
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lead to more memory T cells.
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and therefore upregulate the IL15 pathway and lead to more memory T cells.
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% TODO this mentions the DOE which is in the next aim
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% TODO this mentions the DOE which is in the next aim
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When analyzing all our experiments comprehensively using causal inference, we
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When analyzing all our experiments comprehensively using causal inference, we
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@ -1531,15 +1534,15 @@ manufacturing companies.
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Finally, while we have demonstrated the DMS system in the context of CAR T
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Finally, while we have demonstrated the DMS system in the context of CAR T
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cells, this method can theoretically be applied to any T cell immunotherapy
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cells, this method can theoretically be applied to any T cell immunotherapy
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which responds to anti-CD3/CD28 mAb and cytokine stimulation. These include
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which responds to anti-CD3/CD28 mAb and cytokine stimulation. These include
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tumor infiltrating lymphocytes (TILs), virus-specific T cells (VSTs), T cells
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\glspl{til}, virus-specific T cells (VSTs), T cells engineered to express
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engineered to express γδTCR (TEGs), γδ T cells, T cells with transduced-TCR, and
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$\upgamma\updelta$TCR (TEGs), $\upgamma\updelta$ T cells, T cells with
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CAR-TCR T cells53–58. Similar to CD19-CARs used in liquid tumors, these T cell
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transduced-TCR, and CAR-TCR T cells53–58. Similar to CD19-CARs used in liquid
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immunotherapies would similarly benefit from the increased proliferative
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tumors, these T cell immunotherapies would similarly benefit from the increased
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capacity, metabolic fitness, migration, and engraftment potential characteristic
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proliferative capacity, metabolic fitness, migration, and engraftment potential
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of naïve and memory phenotypes59–61. Indeed, since these T cell immunotherapies
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characteristic of naïve and memory phenotypes59–61. Indeed, since these T cell
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are activated and expanded with either soluble mAbs or bead-immobilized mAbs,
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immunotherapies are activated and expanded with either soluble mAbs or
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our system will likely serve as a drop-in substitution to provide these
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bead-immobilized mAbs, our system will likely serve as a drop-in substitution to
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benefits.
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provide these benefits.
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\chapter{aim 2}\label{aim2}
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\chapter{aim 2}\label{aim2}
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